P047 Castration promotes radiosensitivity by direct regulation of DNA repair in prostate cancer

Al-Ubaidi, Firas L. T.; Schultz, Neil M.; Hamberg, Hans; Granfors, Torvald; Helleday, Thomas

doi:10.1016/s1569-9056(14)61270-7

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“…Findings here revealed a strong association between androgen induced CRY1 and poor outcome. These observations are critical, as androgen depletion is standard of care for combination with radiotherapy in locally advanced PCa to suppress AR activity, which impairs DNA repair [57][58][59] . Furthermore, CRY1 expression strongly correlates with HR factors identified herein as CRY1 regulated (ATM, MRE11A, and RAD50), reinforcing the observation that CRY1 directly regulates HR gene expression to mediate DNA repair.…”

Section: Discussionmentioning

confidence: 99%

The circadian cryptochrome, CRY1, is a pro-tumorigenic factor that rhythmically modulates DNA repair

et al. 2021

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Mechanisms regulating DNA repair processes remain incompletely defined. Here, the circadian factor CRY1, an evolutionally conserved transcriptional coregulator, is identified as a tumor specific regulator of DNA repair. Key findings demonstrate that CRY1 expression is androgen-responsive and associates with poor outcome in prostate cancer. Functional studies and first-in-field mapping of the CRY1 cistrome and transcriptome reveal that CRY1 regulates DNA repair and the G2/M transition. DNA damage stabilizes CRY1 in cancer (in vitro, in vivo, and human tumors ex vivo), which proves critical for efficient DNA repair. Further mechanistic investigation shows that stabilized CRY1 temporally regulates expression of genes required for homologous recombination. Collectively, these findings reveal that CRY1 is hormone-induced in tumors, is further stabilized by genomic insult, and promotes DNA repair and cell survival through temporal transcriptional regulation. These studies identify the circadian factor CRY1 as pro-tumorigenic and nominate CRY1 as a new therapeutic target.

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Section: Discussionmentioning

confidence: 99%