PO.MCB05.02 · 分子与细胞生物学
昼夜节律隐花色素1（CRY1）与前列腺癌（PCa）中DNA修复的相互作用
Interplay of circadian cryptochrome 1 (CRY1) and DNA repair in prostate cancer (PCa)
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：昼夜节律的紊乱与前列腺癌（PCa）相关。先前的研究表明，核心昼夜节律钟因子隐花色素1（CRY1）具有促肿瘤作用，并与PCa的不良临床结局相关。除了其转录共调控功能外，CRY1最近被鉴定为晚期PCa中DNA损伤修复（DDR）的调节因子。分子和药理学上对CRY1的抑制会损害PCa细胞生长，诱导G2/M期阻滞，并破坏同源重组（HR）介导的DNA修复。然而，CRY1在疾病从激素治疗敏感（HTS）向去势抵抗性前列腺癌（CRPC）进展中的机制作用仍未完全明确。
方法：我们使用多西环素可诱导的CRY1敲低模型，分别以LNCaP细胞系代表HTS、以C4-2细胞系代表CRPC，并结合药理学策略来重现生理相关的CRY1调节。使用转录组分析、以DDR为重点的CRISPR敲除（KO）筛选以及下游功能试验，来界定跨疾病阶段的CRY1依赖性转录和修复程序。这有助于鉴定潜在的新型靶向疗法，并预测患者对DDR靶向治疗的反应。
结果：转录组分析揭示了HTS与CRPC模型中不同的CRY1调控基因网络。在HTS中，CRY1活性与包括碱基切除修复、错配修复和G2/M检查点调控在内的通路相关，而在CRPC中，CRY1则特异性地与HR介导的DNA修复相关联。以DDR为靶标的CRISPR筛选进一步表明，CRY1在HTS中通过核苷酸切除修复促进肿瘤发生，而在CRPC中转向依赖HR，提示由CRY1驱动的修复通路选择存在阶段特异性的重塑。这些发现确定了一种跨PCa进展的DDR调控新机制。
结论：总之，我们的研究揭示CRY1通过HTS和CRPC中不同的DDR机制支持PCa进展。因此，单独或与DDR抑制剂联合靶向CRY1，为PCa提供了一种根据疾病阶段量身定制的有前景的治疗策略。
查看英文原文 English abstract
Background: Disruptions in circadian rhythm are linked to prostate cancer (PCa). Previous studies indicate that the core circadian clock factor cryptochrome 1 (CRY1) is pro-tumorigenic and associated with poor clinical outcomes in PCa. Beyond its transcriptional co-regulatory function, CRY1 was recently identified as a modulator of DNA damage repair (DDR) in advanced PCa. Molecular and pharmacological suppression of CRY1 impairs PCa cell growth, induces G2/M arrest, and disrupts homologous recombination (HR)-mediated DNA repair. However, the mechanistic role of CRY1 in disease progression from hormone therapy sensitive (HTS) to castration resistant prostate cancer (CRPC) remains incompletely defined.
Methods: We employed doxycycline-inducible CRY1 knockdown models of both HTS, using LNCaP cell line, and CRPC, using C4-2 cell line, along with pharmacological strategies to recapitulate physiologically relevant CRY1 modulation. Transcriptomic profiling, DDR-focused CRISPR knockout (KO) screening, and downstream functional assays were used to define CRY1-dependent transcriptional and repair programs across disease stages. This allows for the identification of potential novel targeted therapies as well as predicts patient response to DDR targeted therapy.
Results: Transcriptomic analyses revealed distinct CRY1-regulated gene networks in HTS versus CRPC models. In HTS, CRY1 activity was associated with pathways including base excision repair, mismatch repair, and G2/M checkpoint regulation, while in CRPC, CRY1 was specifically linked to HR-mediated DNA repair. DDR-targeted CRISPR screening further demonstrated that CRY1 promotes tumorigenesis via nucleotide excision repair in HTS and shifts to HR reliance in CRPC, suggesting stage-specific rewiring of repair pathway choice driven by CRY1. These findings identify a novel mechanism of DDR regulation across PCa progression.
Conclusions: In sum, our study reveals that CRY1 supports PCa progression via distinct DDR mechanisms in HTS and CRPC. Thus, targeting CRY1, alonge or in combination with DDR inhibitors, offers a promising therapeutic strategy tailored to disease stage in PCa.
利益披露 Disclosure
A. Fallatah, None..
S. DiFazio, None..
L. Ravindranath, None..
O. Richter, None..
C. McNair, None..
A. Shafi, None.