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• W3104397732 endingPage "316" @default.
• W3104397732 startingPage "301" @default.
• W3104397732 abstract "In advanced prostate cancer, resistance to androgen deprivation therapy is achieved through numerous mechanisms, including loss of the androgen receptor (AR) allowing for AR-independent growth. Therapeutic options are limited for AR-independent castration-resistant prostate cancer (CRPC), and defining mechanisms critical for survival is of utmost importance for targeting this lethal disease. Our studies focus on identifying telomere maintenance mechanism (TMM) hallmarks adopted by CRPC to promote survival. TMMs are responsible for telomere elongation to instill replicative immortality and prevent senescence, with the two TMM pathways available being telomerase and alternative lengthening of telomeres (ALT). Here, we show that AR-independent CRPC demonstrates an atypical ALT-like phenotype with variable telomerase expression and activity, whereas AR-dependent models lack discernible ALT hallmarks. In addition, AR-independent CRPC cells exhibited elevated levels of SLX4IP, a protein implicated in promoting ALT. SLX4IP overexpression in AR-dependent C4-2B cells promoted an ALT-like phenotype and telomere maintenance. SLX4IP knockdown in AR-independent DU145 and PC-3 cells led to ALT-like hallmark reduction, telomere shortening, and induction of senescence. In PC-3 xenografts, this effect translated to reduced tumor volume. Using an in vitro model of AR-independent progression, loss of AR in AR-dependent C4-2B cells promoted an atypical ALT-like phenotype in an SLX4IP-dependent manner. Insufficient SLX4IP expression diminished ALT-like hallmarks and resulted in accelerated telomere loss and senescence. IMPLICATIONS: This study demonstrates a unique reliance of AR-independent CRPC on SLX4IP-mediated ALT-like hallmarks and loss of these hallmarks induces telomere shortening and senescence, thereby impairing replicative immortality." @default.
• W3104397732 created "2020-11-23" @default.
• W3104397732 creator A5002785674 @default.
• W3104397732 creator A5019884676 @default.
• W3104397732 creator A5043963081 @default.
• W3104397732 creator A5045731475 @default.
• W3104397732 date "2021-02-01" @default.
• W3104397732 modified "2023-10-18" @default.
• W3104397732 title "SLX4IP Promotes Telomere Maintenance in Androgen Receptor–Independent Castration-Resistant Prostate Cancer through ALT-like Telomeric PML Localization" @default.
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• W3104397732 doi "https://doi.org/10.1158/1541-7786.mcr-20-0314" @default.
• W3104397732 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8086381" @default.
• W3104397732 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/33188147" @default.
• W3104397732 hasPublicationYear "2021" @default.
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