Abstract SY33-02: The circadian cryptochrome, CRY1, is a pro-tumorigenic factor that rhythmically modulates DNA repair

Abstract

Abstract The second leading cause of cancer-related death in US men is prostate cancer (PCa), which is an androgen-dependent disease in which the androgen receptor (AR) plays an important role. Recent studies have underscored the importance of AR-mediated DNA repair factor regulation as strongly associated with poor outcome in PCa, yet the mechanistic underpinnings of the molecular and cellular consequence of AR-regulated DNA repair and tumor progression have yet to be fully defined. Mining of comprehensive studies designed to identify AR functions critical for PCa revealed that AR binds to multiple regulatory elements within the CRY1 (cryptochrome 1) locus, as observed in several hormone therapy-sensitive PCa models.Here, the circadian factor CRY1, an evolutionally conserved transcriptional coregulator, is identified as a tumor specific regulator of DNA repair. Intriguingly, the N-terminus of CRY1 is a photolyase homology domain suggesting a potential role for CRY1 in DNA damage response. Circadian factors have been implicated in diverse non-canonical physiological functions such as DNA repair, DNA damage checkpoints, and apoptosis. Given the potential implications of CRY1 and DNA repair interplay, this study sought to delineate the molecular and biological consequences of androgen-responsive CRY1 in cancer through cistromic, transcriptomic, and molecular modeling of CRY1 dysregulation in PCa. 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. This work was recently published in Nature Communications (Shafi et al, 2021).Ongoing and future work with elucidate the role of CRY1 in PCa by identifying CRY1-driven pathways impacting DNA damage repair (DDR) regulation and CRY1 function on tumor progression and therapeutic response to discern novel pathways to improve existing therapies. Our ongoing work has the potential for broad implications for understanding and treating lethal PCa. Based on our preliminary data, we hypothesize that CRY1 is key modulator of DDR impacting PCa growth and survival, and that delineating the underlying molecular mechanisms of CRY1 and DDR interplay will allow for improved management of advanced disease. Our data indicate that CRY1 expression is altered in PCa, associated with poor outcome, and elicits pro-tumorigenic phenotypes through direct DDR regulation. Our continued work will define the biology of lethal PCa by delineating the molecular and cellular consequence of tumor-associated CRY1 deregulation, providing insight into the function of CRY1 on DNA repair competency. Also, this study will uncover mechanisms of action and identify novel partners for CRY1 function to transcriptionally regulate DNA repair and cancer progression. Lastly, the translational studies from this research study will elucidate the impact of CRY1 function on tumor progression and therapeutic response. Thus, these findings will reveal potential molecular and clinical biomarkers for patients and will ultimately aid in improving existing therapies and developing effective treatments to reduce death from PCa. The long-term impact of CRY1 as a pro-tumorigenic factor driving PCa progression and lethality, emphasizes the importance of developing treatments targeting this factor to mitigate aggressive disease. This study will be crucial in providing novel insight into CRY1 function in human PCa tumors to identify new avenues for therapeutic intervention. This research represents critical steps to understand how circadian factors, specifically CRY1, mediate DNA repair and promote tumorigenesis. Through our collaboration with circadian and DDR experts, this impactful work will not only provide deep mechanistic insight into CRY1 function in PCa, but also lay the foundation for preclinical studies aimed at developing novel strategies for treating CRY1-deregulated cancers. Thus, this ongoing research has immense translational impact serving as the basis for new investigator-initiated clinical trials and altering regimens to emphasize the importance of chronotherapy enhancing standard-of-care to ultimately improve outcome and reduce lethality of PCa. Citation Format: Ayesha Shafi. The circadian cryptochrome, CRY1, is a pro-tumorigenic factor that rhythmically modulates DNA repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY33-02.