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• W2034806022 abstract "Lin28A and Lin28B selectively block the expression of let-7 microRNAs and function as oncogenes in a variety of human cancers. Lin28A recruits a TUTase (Zcchc11/TUT4) to let-7 precursors to block processing by Dicer in the cell cytoplasm. Here we find that unlike Lin28A, Lin28B represses let-7 processing through a Zcchc11-independent mechanism. Lin28B functions in the nucleus by sequestering primary let-7 transcripts and inhibiting their processing by the Microprocessor. The inhibitory effects of Zcchc11 depletion on the tumorigenic capacity and metastatic potential of human cancer cells and xenografts are restricted to Lin28A-expressing tumors. Furthermore, the majority of human colon and breast tumors analyzed exclusively express either Lin28A or Lin28B. Lin28A is expressed in HER2-overexpressing breast tumors, whereas Lin28B expression characterizes triple-negative breast tumors. Overall our results illuminate the distinct mechanisms by which Lin28A and Lin28B function and have implications for the development of new strategies for cancer therapy. Lin28A and Lin28B selectively block the expression of let-7 microRNAs and function as oncogenes in a variety of human cancers. Lin28A recruits a TUTase (Zcchc11/TUT4) to let-7 precursors to block processing by Dicer in the cell cytoplasm. Here we find that unlike Lin28A, Lin28B represses let-7 processing through a Zcchc11-independent mechanism. Lin28B functions in the nucleus by sequestering primary let-7 transcripts and inhibiting their processing by the Microprocessor. The inhibitory effects of Zcchc11 depletion on the tumorigenic capacity and metastatic potential of human cancer cells and xenografts are restricted to Lin28A-expressing tumors. Furthermore, the majority of human colon and breast tumors analyzed exclusively express either Lin28A or Lin28B. Lin28A is expressed in HER2-overexpressing breast tumors, whereas Lin28B expression characterizes triple-negative breast tumors. Overall our results illuminate the distinct mechanisms by which Lin28A and Lin28B function and have implications for the development of new strategies for cancer therapy. The TUTase Zcchc11 represses expression of the miRNA let-7 via Lin28A but not Lin28B Lin28B localizes to the cell nucleus and blocks pri-let-7 processing Zcchc11 depletion selectively inhibits the tumorigenicity of Lin28A-expressing cancer The majority of human colon and breast tumors express either Lin28A or Lin28B Control of gene expression by microRNAs (miRNAs) is important for normal development. Altered miRNA expression is linked with various diseases including cancer (Small and Olson, 2011Small E.M. Olson E.N. Pervasive roles of microRNAs in cardiovascular biology.Nature. 2011; 469: 336-342Crossref PubMed Scopus (982) Google Scholar). miRNA biogenesis begins with transcription of primary transcripts (pri-miRNAs) that contain a stem-loop structure. In the cell nucleus, pri-miRNAs are processed by the Microprocessor, containing the ribonuclease Drosha and its essential cofactor DGCR8 (Denli et al., 2004Denli A.M. Tops B.B. Plasterk R.H. Ketting R.F. Hannon G.J. Processing of primary microRNAs by the Microprocessor complex.Nature. 2004; 432: 231-235Crossref PubMed Scopus (2004) Google Scholar, Gregory et al., 2004Gregory R.I. Yan K.P. Amuthan G. Chendrimada T. Doratotaj B. Cooch N. Shiekhattar R. The Microprocessor complex mediates the genesis of microRNAs.Nature. 2004; 432: 235-240Crossref PubMed Scopus (2103) Google Scholar). The Microprocessor cleaves the double-stranded RNA toward the base of the stem loop to release a 60–80 nucleotide (nt) precursor (pre-miRNA) that is exported to the cell cytoplasm and cleaved by Dicer to generate a 22 nt duplex (Hutvágner et al., 2001Hutvágner G. McLachlan J. Pasquinelli A.E. Bálint E. Tuschl T. Zamore P.D. A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA.Science. 2001; 293: 834-838Crossref PubMed Scopus (2175) Google Scholar, Krol et al., 2010Krol J. Loedige I. Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay.Nat. Rev. Genet. 2010; 11: 597-610Crossref PubMed Scopus (3542) Google Scholar). One RNA strand is bound by Argonaute and incorporated into the RNA-induced silencing complex (RISC) (Gregory et al., 2005Gregory R.I. Chendrimada T.P. Cooch N. Shiekhattar R. Human RISC couples microRNA biogenesis and posttranscriptional gene silencing.Cell. 2005; 123: 631-640Abstract Full Text Full Text PDF PubMed Scopus (1227) Google Scholar, Liu et al., 2004Liu J. Carmell M.A. Rivas F.V. Marsden C.G. Thomson J.M. Song J.J. Hammond S.M. Joshua-Tor L. Hannon G.J. Argonaute2 is the catalytic engine of mammalian RNAi.Science. 2004; 305: 1437-1441Crossref PubMed Scopus (2035) Google Scholar). Basepairing between the miRNA and target mRNA guides RISC to complementary transcripts, leading to gene repression through mRNA degradation and/or translational repression (Krol et al., 2010Krol J. Loedige I. Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay.Nat. Rev. Genet. 2010; 11: 597-610Crossref PubMed Scopus (3542) Google Scholar). Altered miRNA expression is directly associated with cancer initiation, progression, and metastasis and is observed in a wide variety of human malignancies (Di Leva and Croce, 2010Di Leva G. Croce C.M. Roles of small RNAs in tumor formation.Trends Mol. Med. 2010; 16: 257-267Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar). The let-7 miRNA family members act as tumor suppressors by inhibiting expression of oncogenes and key regulators of mitogenic pathways including RAS, MYC, and HMGA2 (Büssing et al., 2008Büssing I. Slack F.J. Grosshans H. let-7 microRNAs in development, stem cells and cancer.Trends Mol. Med. 2008; 14: 400-409Abstract Full Text Full Text PDF PubMed Scopus (499) Google Scholar). let-7 is downregulated in numerous different cancers, and low let-7 correlates with poor prognosis (Boyerinas et al., 2010Boyerinas B. Park S.M. Hau A. Murmann A.E. Peter M.E. The role of let-7 in cell differentiation and cancer.Endocr. Relat. Cancer. 2010; 17: F19-F36Crossref PubMed Scopus (559) Google Scholar, Shell et al., 2007Shell S. Park S.M. Radjabi A.R. Schickel R. Kistner E.O. Jewell D.A. Feig C. Lengyel E. Peter M.E. Let-7 expression defines two differentiation stages of cancer.Proc. Natl. Acad. Sci. USA. 2007; 104: 11400-11405Crossref PubMed Scopus (412) Google Scholar, Takamizawa et al., 2004Takamizawa J. Konishi H. Yanagisawa K. Tomida S. Osada H. Endoh H. Harano T. Yatabe Y. Nagino M. Nimura Y. et al.Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival.Cancer Res. 2004; 64: 3753-3756Crossref PubMed Scopus (2151) Google Scholar). Restoration of let-7 expression effectively inhibits cancer growth in mouse models of lung and breast cancers (Barh et al., 2010Barh D. Malhotra R. Ravi B. Sindhurani P. MicroRNA let-7: an emerging next-generation cancer therapeutic.Curr. Oncol. 2010; 17: 70-80Crossref PubMed Scopus (210) Google Scholar, Esquela-Kerscher et al., 2008Esquela-Kerscher A. Trang P. Wiggins J.F. Patrawala L. Cheng A. Ford L. Weidhaas J.B. Brown D. Bader A.G. Slack F.J. The let-7 microRNA reduces tumor growth in mouse models of lung cancer.Cell Cycle. 2008; 7: 759-764Crossref PubMed Scopus (564) Google Scholar, Slack, 2009Slack F. let-7 microRNA reduces tumor growth.Cell Cycle. 2009; 8: 1823Crossref PubMed Scopus (13) Google Scholar, Trang et al., 2010Trang P. Medina P.P. Wiggins J.F. Ruffino L. Kelnar K. Omotola M. Homer R. Brown D. Bader A.G. Weidhaas J.B. Slack F.J. Regression of murine lung tumors by the let-7 microRNA.Oncogene. 2010; 29: 1580-1587Crossref PubMed Scopus (432) Google Scholar, Yu et al., 2007aYu F. Yao H. Zhu P. Zhang X. Pan Q. Gong C. Huang Y. Hu X. Su F. Lieberman J. Song E. let-7 regulates self renewal and tumorigenicity of breast cancer cells.Cell. 2007; 131: 1109-1123Abstract Full Text Full Text PDF PubMed Scopus (1643) Google Scholar). In humans, there are 12 let-7 family members (let-7a-1, -2, -3; let-7b; let-7c; let-7d; let-7e; let-7f-1, -2; let-7g; let-7i; miR-98) located at eight different chromosomal loci. Of note, many tumors are characterized by the coordinate downregulation of multiple let-7 miRNAs (Shell et al., 2007Shell S. Park S.M. Radjabi A.R. Schickel R. Kistner E.O. Jewell D.A. Feig C. Lengyel E. Peter M.E. Let-7 expression defines two differentiation stages of cancer.Proc. Natl. Acad. Sci. USA. 2007; 104: 11400-11405Crossref PubMed Scopus (412) Google Scholar). The developmentally regulated RNA-binding protein Lin28 was found to selectively repress expression of let-7 miRNAs (Heo et al., 2008Heo I. Joo C. Cho J. Ha M. Han J. Kim V.N. Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA.Mol. Cell. 2008; 32: 276-284Abstract Full Text Full Text PDF PubMed Scopus (780) Google Scholar, Newman et al., 2008Newman M.A. Thomson J.M. Hammond S.M. Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing.RNA. 2008; 14: 1539-1549Crossref PubMed Scopus (598) Google Scholar, Rybak et al., 2008Rybak A. Fuchs H. Smirnova L. Brandt C. Pohl E.E. Nitsch R. Wulczyn F.G. A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment.Nat. Cell Biol. 2008; 10: 987-993Crossref PubMed Scopus (658) Google Scholar, Viswanathan et al., 2008Viswanathan S.R. Daley G.Q. Gregory R.I. Selective blockade of microRNA processing by Lin28.Science. 2008; 320: 97-100Crossref PubMed Scopus (1187) Google Scholar). This posttranscriptional regulation of let-7 by Lin28 is required for normal development and contributes to the pluripotent state by preventing let-7-mediated differentiation of embryonic stem cells (ESCs). Lin28 overexpression or let-7 inhibition with antisense RNAs promotes reprogramming of human and mouse fibroblasts to induced pluripotent stem cells (iPSCs) (Martinez and Gregory, 2010Martinez N.J. Gregory R.I. MicroRNA gene regulatory pathways in the establishment and maintenance of ESC identity.Cell Stem Cell. 2010; 7: 31-35Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, Melton et al., 2010Melton C. Judson R.L. Blelloch R. Opposing microRNA families regulate self-renewal in mouse embryonic stem cells.Nature. 2010; 463: 621-626Crossref PubMed Scopus (556) Google Scholar, Yu et al., 2007bYu J. Vodyanik M.A. Smuga-Otto K. Antosiewicz-Bourget J. Frane J.L. Tian S. Nie J. Jonsdottir G.A. Ruotti V. Stewart R. et al.Induced pluripotent stem cell lines derived from human somatic cells.Science. 2007; 318: 1917-1920Crossref PubMed Scopus (8146) Google Scholar). Unlike in C. elegans where a single Lin28 gene is responsible for repression of let-7 expression and control of developmental timing, the mammalian genome encodes two Lin28 paralogs, Lin28 (hereafter Lin28A) and Lin28B (Guo et al., 2006Guo Y. Chen Y. Ito H. Watanabe A. Ge X. Kodama T. Aburatani H. Identification and characterization of lin-28 homolog B (LIN28B) in human hepatocellular carcinoma.Gene. 2006; 384: 51-61Crossref PubMed Scopus (231) Google Scholar, Lehrbach et al., 2009Lehrbach N.J. Armisen J. Lightfoot H.L. Murfitt K.J. Bugaut A. Balasubramanian S. Miska E.A. LIN-28 and the poly(U) polymerase PUP-2 regulate let-7 microRNA processing in Caenorhabditis elegans.Nat. Struct. Mol. Biol. 2009; 16: 1016-1020Crossref PubMed Scopus (200) Google Scholar, Moss et al., 1997Moss E.G. Lee R.C. Ambros V. The cold shock domain protein LIN-28 controls developmental timing in C. elegans and is regulated by the lin-4 RNA.Cell. 1997; 88: 637-646Abstract Full Text Full Text PDF PubMed Scopus (684) Google Scholar, Van Wynsberghe et al., 2011Van Wynsberghe P.M. Kai Z.S. Massirer K.B. Burton V.H. Yeo G.W. Pasquinelli A.E. LIN-28 co-transcriptionally binds primary let-7 to regulate miRNA maturation in Caenorhabditis elegans.Nat. Struct. Mol. Biol. 2011; 18: 302-308Crossref PubMed Scopus (101) Google Scholar, Viswanathan and Daley, 2010Viswanathan S.R. Daley G.Q. Lin28: A microRNA regulator with a macro role.Cell. 2010; 140: 445-449Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar). Lin28B also represses expression of multiple let-7 members, and genome-wide association studies (GWAS) have linked Lin28B with the determination of human height and control of the age of onset of puberty and menopause, phenotypes that are recapitulated in a mouse model (Zhu et al., 2010Zhu H. Shah S. Shyh-Chang N. Shinoda G. Einhorn W.S. Viswanathan S.R. Takeuchi A. Grasemann C. Rinn J.L. Lopez M.F. et al.Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies.Nat. Genet. 2010; 42: 626-630Crossref PubMed Scopus (242) Google Scholar). Activation of Lin28A/Lin28B occurs in several different primary human tumors, and these tumors display low levels of let-7 expression (Iliopoulos et al., 2009Iliopoulos D. Hirsch H.A. Struhl K. An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation.Cell. 2009; 139: 693-706Abstract Full Text Full Text PDF PubMed Scopus (1156) Google Scholar, Viswanathan et al., 2009Viswanathan S.R. Powers J.T. Einhorn W. Hoshida Y. Ng T.L. Toffanin S. O'Sullivan M. Lu J. Phillips L.A. Lockhart V.L. et al.Lin28 promotes transformation and is associated with advanced human malignancies.Nat. Genet. 2009; 41: 843-848Crossref PubMed Scopus (664) Google Scholar). Indeed, Lin28A/Lin28B function as oncogenes that promote cellular transformation when ectopically expressed (Iliopoulos et al., 2009Iliopoulos D. Hirsch H.A. Struhl K. An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation.Cell. 2009; 139: 693-706Abstract Full Text Full Text PDF PubMed Scopus (1156) Google Scholar, Viswanathan et al., 2009Viswanathan S.R. Powers J.T. Einhorn W. Hoshida Y. Ng T.L. Toffanin S. O'Sullivan M. Lu J. Phillips L.A. Lockhart V.L. et al.Lin28 promotes transformation and is associated with advanced human malignancies.Nat. Genet. 2009; 41: 843-848Crossref PubMed Scopus (664) Google Scholar, West et al., 2009West J.A. Viswanathan S.R. Yabuuchi A. Cunniff K. Takeuchi A. Park I.H. Sero J.E. Zhu H. Perez-Atayde A. Frazier A.L. et al.A role for Lin28 in primordial germ-cell development and germ-cell malignancy.Nature. 2009; 460: 909-913Crossref PubMed Scopus (316) Google Scholar). Importantly, this effect is abrogated when let-7 is reintroduced into these cells (Iliopoulos et al., 2009Iliopoulos D. Hirsch H.A. Struhl K. An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation.Cell. 2009; 139: 693-706Abstract Full Text Full Text PDF PubMed Scopus (1156) Google Scholar, Viswanathan et al., 2009Viswanathan S.R. Powers J.T. Einhorn W. Hoshida Y. Ng T.L. Toffanin S. O'Sullivan M. Lu J. Phillips L.A. Lockhart V.L. et al.Lin28 promotes transformation and is associated with advanced human malignancies.Nat. Genet. 2009; 41: 843-848Crossref PubMed Scopus (664) Google Scholar). Therefore, Lin28-mediated cellular transformation is directly dependent on let-7 levels. Conversely, depletion of Lin28A or Lin28B in human cancer cells results in decreased cell proliferation (Chang et al., 2009Chang T.C. Zeitels L.R. Hwang H.W. Chivukula R.R. Wentzel E.A. Dews M. Jung J. Gao P. Dang C.V. Beer M.A. et al.Lin-28B transactivation is necessary for Myc-mediated let-7 repression and proliferation.Proc. Natl. Acad. Sci. USA. 2009; 106: 3384-3389Crossref PubMed Scopus (322) Google Scholar, Iliopoulos et al., 2009Iliopoulos D. Hirsch H.A. Struhl K. An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation.Cell. 2009; 139: 693-706Abstract Full Text Full Text PDF PubMed Scopus (1156) Google Scholar, Viswanathan et al., 2009Viswanathan S.R. Powers J.T. Einhorn W. Hoshida Y. Ng T.L. Toffanin S. O'Sullivan M. Lu J. Phillips L.A. Lockhart V.L. et al.Lin28 promotes transformation and is associated with advanced human malignancies.Nat. Genet. 2009; 41: 843-848Crossref PubMed Scopus (664) Google Scholar). Lin28A/Lin28B may contribute to the development of aggressive, poorly differentiated tumors because their expression is associated with advanced disease in hepatocellular carcinoma (HCC), chronic myeloid leukemia (CML), Wilms' tumor, ovarian carcinoma, colon adenocarcinoma, and germ cell tumors (Dangi-Garimella et al., 2009Dangi-Garimella S. Yun J. Eves E.M. Newman M. Erkeland S.J. Hammond S.M. Minn A.J. Rosner M.R. Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7.EMBO J. 2009; 28: 347-358Crossref PubMed Scopus (315) Google Scholar, Guo et al., 2006Guo Y. Chen Y. Ito H. Watanabe A. Ge X. Kodama T. Aburatani H. Identification and characterization of lin-28 homolog B (LIN28B) in human hepatocellular carcinoma.Gene. 2006; 384: 51-61Crossref PubMed Scopus (231) Google Scholar, Iliopoulos et al., 2009Iliopoulos D. Hirsch H.A. Struhl K. An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation.Cell. 2009; 139: 693-706Abstract Full Text Full Text PDF PubMed Scopus (1156) Google Scholar, Ji and Wang, 2010Ji J. Wang X.W. A Yin-Yang balancing act of the lin28/let-7 link in tumorigenesis.J. Hepatol. 2010; 53: 974-975Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, King et al., 2011King C.E. Cuatrecasas M. Castells A. Sepulveda A.R. Lee J.S. Rustgi A.K. LIN28B promotes colon cancer progression and metastasis.Cancer Res. 2011; 71: 4260-4268Crossref PubMed Scopus (186) Google Scholar, Liang et al., 2010Liang L. Wong C.M. Ying Q. Fan D.N. Huang S. Ding J. Yao J. Yan M. Li J. Yao M. et al.MicroRNA-125b suppressesed human liver cancer cell proliferation and metastasis by directly targeting oncogene LIN28B2.Hepatology. 2010; 52: 1731-1740Crossref PubMed Scopus (225) Google Scholar, Lu et al., 2009Lu L. Katsaros D. Shaverdashvili K. Qian B. Wu Y. de la Longrais I.A. Preti M. Menato G. Yu H. Pluripotent factor lin-28 and its homologue lin-28b in epithelial ovarian cancer and their associations with disease outcomes and expression of let-7a and IGF-II.Eur. J. Cancer. 2009; 45: 2212-2218Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, Oh et al., 2010Oh J.S. Kim J.J. Byun J.Y. Kim I.A. Lin28-let7 modulates radiosensitivity of human cancer cells with activation of K-Ras.Int. J. Radiat. Oncol. Biol. Physiol. 2010; 76: 5-8Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, Peng et al., 2010Peng S. Maihle N.J. Huang Y. Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer.Oncogene. 2010; 29: 2153-2159Crossref PubMed Scopus (216) Google Scholar, Viswanathan et al., 2009Viswanathan S.R. Powers J.T. Einhorn W. Hoshida Y. Ng T.L. Toffanin S. O'Sullivan M. Lu J. Phillips L.A. Lockhart V.L. et al.Lin28 promotes transformation and is associated with advanced human malignancies.Nat. Genet. 2009; 41: 843-848Crossref PubMed Scopus (664) Google Scholar, Wang et al., 2010Wang Y.C. Chen Y.L. Yuan R.H. Pan H.W. Yang W.C. Hsu H.C. Jeng Y.M. Lin-28B expression promotes transformation and invasion in human hepatocellular carcinoma.Carcinogenesis. 2010; 31: 1516-1522Crossref PubMed Scopus (88) Google Scholar, West et al., 2009West J.A. Viswanathan S.R. Yabuuchi A. Cunniff K. Takeuchi A. Park I.H. Sero J.E. Zhu H. Perez-Atayde A. Frazier A.L. et al.A role for Lin28 in primordial germ-cell development and germ-cell malignancy.Nature. 2009; 460: 909-913Crossref PubMed Scopus (316) Google Scholar, Yang et al., 2010Yang X. Lin X. Zhong X. Kaur S. Li N. Liang S. Lassus H. Wang L. Katsaros D. Montone K. et al.Double-negative feedback loop between reprogramming factor LIN28 and microRNA let-7 regulates aldehyde dehydrogenase 1-positive cancer stem cells.Cancer Res. 2010; 70: 9463-9472Crossref PubMed Scopus (136) Google Scholar) and is associated with poor clinical outcome and patient survival in HCC, colon, and ovarian cancer (King et al., 2011King C.E. Cuatrecasas M. Castells A. Sepulveda A.R. Lee J.S. Rustgi A.K. LIN28B promotes colon cancer progression and metastasis.Cancer Res. 2011; 71: 4260-4268Crossref PubMed Scopus (186) Google Scholar, Lu et al., 2009Lu L. Katsaros D. Shaverdashvili K. Qian B. Wu Y. de la Longrais I.A. Preti M. Menato G. Yu H. Pluripotent factor lin-28 and its homologue lin-28b in epithelial ovarian cancer and their associations with disease outcomes and expression of let-7a and IGF-II.Eur. J. Cancer. 2009; 45: 2212-2218Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, Viswanathan et al., 2009Viswanathan S.R. Powers J.T. Einhorn W. Hoshida Y. Ng T.L. Toffanin S. O'Sullivan M. Lu J. Phillips L.A. Lockhart V.L. et al.Lin28 promotes transformation and is associated with advanced human malignancies.Nat. Genet. 2009; 41: 843-848Crossref PubMed Scopus (664) Google Scholar). In the case of Lin28B, rare amplification or translocation events might explain activation in some cases (Viswanathan et al., 2009Viswanathan S.R. Powers J.T. Einhorn W. Hoshida Y. Ng T.L. Toffanin S. O'Sullivan M. Lu J. Phillips L.A. Lockhart V.L. et al.Lin28 promotes transformation and is associated with advanced human malignancies.Nat. Genet. 2009; 41: 843-848Crossref PubMed Scopus (664) Google Scholar). A more common mechanism might be transcriptional activation by upstream factors. For example, c-Myc binds to both Lin28A and Lin28B loci and activates expression of these genes (Chang et al., 2009Chang T.C. Zeitels L.R. Hwang H.W. Chivukula R.R. Wentzel E.A. Dews M. Jung J. Gao P. Dang C.V. Beer M.A. et al.Lin-28B transactivation is necessary for Myc-mediated let-7 repression and proliferation.Proc. Natl. Acad. Sci. USA. 2009; 106: 3384-3389Crossref PubMed Scopus (322) Google Scholar). In a breast cancer model, transient expression of Src oncoprotein results in a transformed cell line that forms self-renewing mammospheres harboring tumor-initiating cells (Iliopoulos et al., 2009Iliopoulos D. Hirsch H.A. Struhl K. An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation.Cell. 2009; 139: 693-706Abstract Full Text Full Text PDF PubMed Scopus (1156) Google Scholar). The transformation process involves NF-κB activation leading to direct transcriptional upregulation of Lin28B, consequent let-7 loss, and derepression of the let-7 target gene IL-6. Because IL-6 activates NF-κB, this regulatory circuit represents a positive feedback loop, providing a molecular link between inflammation and cancer. Selective regulation of let-7 expression involves Lin28A binding to the terminal loop of let-7 precursors, a molecular recognition that requires both the cold shock domain (CSD) and CCHC-type zinc finger RNA-binding domains of the Lin28A protein (Piskounova et al., 2008Piskounova E. Viswanathan S.R. Janas M. LaPierre R.J. Daley G.Q. Sliz P. Gregory R.I. Determinants of microRNA processing inhibition by the developmentally regulated RNA-binding protein Lin28.J. Biol. Chem. 2008; 283: 21310-21314Crossref PubMed Scopus (285) Google Scholar). Lin28A recruits the activity of a terminal uridylyltransferase (TUTase), Zcchc11 (also known as TUTase4 or TUT4), that inhibits pre-let-7 processing by Dicer and leads to the rapid decay of oligouridylated pre-let-7 RNAs (Hagan et al., 2009Hagan J.P. Piskounova E. Gregory R.I. Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in mouse embryonic stem cells.Nat. Struct. Mol. Biol. 2009; 16: 1021-1025Crossref PubMed Scopus (410) Google Scholar, Heo et al., 2009Heo I. Joo C. Kim Y.K. Ha M. Yoon M.J. Cho J. Yeom K.H. Han J. Kim V.N. TUT4 in concert with Lin28 suppresses microRNA biogenesis through pre-microRNA uridylation.Cell. 2009; 138: 696-708Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar). Although both Lin28A and Lin28B can recruit Zcchc11/TUT4 to uridylate pre-let-7 in vitro, the molecular mechanism of the Lin28B-mediated blockade of let-7 expression has yet to be determined (Heo et al., 2008Heo I. Joo C. Cho J. Ha M. Han J. Kim V.N. Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA.Mol. Cell. 2008; 32: 276-284Abstract Full Text Full Text PDF PubMed Scopus (780) Google Scholar, Heo et al., 2009Heo I. Joo C. Kim Y.K. Ha M. Yoon M.J. Cho J. Yeom K.H. Han J. Kim V.N. TUT4 in concert with Lin28 suppresses microRNA biogenesis through pre-microRNA uridylation.Cell. 2009; 138: 696-708Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar). Here we investigate the regulation of let-7 expression by Lin28B. Surprisingly, we find that despite their high degree of homology, Lin28A and Lin28B function through distinct mechanisms. Depletion of Zcchc11 affects let-7 expression only in Lin28A-expressing cancer cells, whereas Lin28B functions through a Zcchc11-independent mechanism. We find that Lin28A and Lin28B are differentially localized in cells with predominantly cytoplasmic Lin28A, whereas due to its functional nuclear localization signals, Lin28B accumulates in the nucleus, where it binds pri-let-7 miRNAs to block processing by the Microprocessor. In contrast, Lin28A functions in the cytoplasm by blocking at the Dicer step and recruiting the TUTase to uridylate pre-let-7. Our findings identify Zcchc11 as a possible therapeutic target in Lin28A-expressing cancers. Accordingly, we demonstrate that Zcchc11 depletion selectively inhibits the tumorigenic capacity and metastatic potential of Lin28A- but not Lin28B-expresing human cancer cells and xenografts. Our results illuminate the distinct mechanisms by which Lin28A and Lin28B function and have broad implications for the development of new strategies for cancer therapy. The paralogous RNA-binding proteins Lin28A and Lin28B have a high degree of sequence identity and conserved domain organization (Figure 1A ), and both proteins selectively block let-7 expression (Newman et al., 2008Newman M.A. Thomson J.M. Hammond S.M. Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing.RNA. 2008; 14: 1539-1549Crossref PubMed Scopus (598) Google Scholar, Viswanathan et al., 2008Viswanathan S.R. Daley G.Q. Gregory R.I. Selective blockade of microRNA processing by Lin28.Science. 2008; 320: 97-100Crossref PubMed Scopus (1187) Google Scholar). We screened several human cancer cell lines and found that some express Lin28A, whereas others express Lin28B (Figure 1B). We did not observe coexpression of both Lin28A and Lin28B in any cell line, suggesting that their expression may be mutually exclusive. We found ubiquitous Zcchc11 expression. HeLa cells express Zcchc11 but neither Lin28A nor Lin28B. Because Lin28A-mediated repression of let-7 in mouse ESCs (mESCs) involves the TUTase Zcchc11, we next asked whether Lin28A and Lin28B function through the same mechanism to block let-7 processing. Previous reports have used recombinant Lin28A and Lin28B interchangeably in biochemical assays, demonstrating that Lin28B is capable of enhancing Zcchc11 activity in vitro; however, the physiological relevance of these observations remains unknown (Heo et al., 2009Heo I. Joo C. Kim Y.K. Ha M. Yoon M.J. Cho J. Yeom K.H. Han J. Kim V.N. TUT4 in concert with Lin28 suppresses microRNA biogenesis through pre-microRNA uridylation.Cell. 2009; 138: 696-708Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar). To begin to investigate whether both Lin28A and Lin28B function through a Zcchc11 TUTase-dependent mechanism, we performed coimmunoprecipitation (co-IP) experiments. Myc-tagged Lin28A, Lin28B, or Ago2 were coexpressed with either Flag-tagged Zcchc11 or Flag-EIF6 control (Figure 1C). Because the Lin28A-Zcchc11 interaction has been shown to be RNA dependent, we also coexpressed pri-let-7g (Heo et al., 2009Heo I. Joo C. Kim Y.K. Ha M. Yoon M.J. Cho J. Yeom K.H. Han J. Kim V.N. TUT4 in concert with Lin28 suppresses microRNA biogenesis through pre-microRNA uridylation.Cell. 2009; 138: 696-708Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar). Consistent with earlier reports, myc-Lin28A was found to be associated with affinity-purified Flag-Zcchc11 (Heo et al., 2009Heo I. Joo C. Kim Y.K. Ha M. Yoon M.J. Cho J. Yeom K.H. Han J. Kim V.N. TUT4 in concert with Lin28 suppresses microRNA biogenesis through pre-microRNA uridylation.Cell. 2009; 138: 696-708Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar). However, we were unable to detect a physical interaction between myc-Lin28B and Flag-Zcchc11. We performed additional co-IP experiments in which we titrated the amount of exogenously expressed Flag-Zcchc11. These experiments confirmed the specific physical interaction of Zcchc11 and Lin28A, whereas myc-Lin28B was not detected in any of the Flag-Zcchc11 IPs (Figure S1A available online). This was additionally confirmed by the co-IP of endogenous Lin28A in Igrov1 cells (Figure S1B). Together, these results indicate that unlike for Lin28A, we could not detect any physical interaction between Lin28B and Zcchc11. Next, to address the functional requirement of Zcchc11 in the Lin28A- and Lin28B-mediated repression of let-7 expression, we performed a series of knockdown experiments to deplete Zcchc11 in a panel of human cancer cell lines. We used shRNAs to deplete Lin28A or Zcchc11 expression in Igrov1 cells and measured the effect on let-7 expression by quantitative reverse transcription PCR (q.RT-PCR). As expected, depletion of Lin28A led to an ∼10-fold increase in let-7 levels. Knockdown of Zcchc11 with three independent shRNAs also led to elevated mature let-7 levels (Figure 1D). Therefore, Zcchc11 is involved in the repression of let-7 expression in this Lin28A-expressing human cancer cell line" @default.
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• W2034806022 date "2011-11-01" @default.
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• W2034806022 title "Lin28A and Lin28B Inhibit let-7 MicroRNA Biogenesis by Distinct Mechanisms" @default.
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• W2034806022 doi "https://doi.org/10.1016/j.cell.2011.10.039" @default.
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