PO.ET06.05 · 实验与分子治疗
BMAL2通过调节同源重组维持DNA完整性以促进卵巢透明细胞癌的肿瘤发生
BMAL2 maintains DNA integrity via regulating homologous recombination to promote ovarian clear cell carcinoma tumorigenesis
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
卵巢癌是全球最致命的妇科恶性肿瘤。在其亚型中，卵巢透明细胞癌（OCCC）以其内在的化疗耐药、预后不良和缺乏有效疗法为特征。迄今为止，只有ARID1A突变的OCCC对PARP抑制剂表现出适度的敏感性，凸显了对新型治疗靶点的迫切需求。在此，我们鉴定出BMAL2——一种昼夜节律转录因子——为OCCC细胞中关键的DNA完整性调节因子。BMAL2耗竭下调了RAD51，损害了同源重组介导的DNA修复，从而抑制了细胞存活和肿瘤生长。为在药理学上靶向BMAL2，我们进行了基于结构的虚拟筛选，鉴定出GW-833972A为一种小分子抑制剂，可有效结合并降解BMAL2蛋白。机制上，GW-833972A介导的BMAL2降解损害了DNA修复并在体内抑制了肿瘤生长。总之，这些发现揭示了BMAL2在OCCC中关键的致癌作用，并证明抑制BMAL2为这种化疗耐药性癌症提供了一种有前景的治疗策略。
查看英文原文 English abstract
Ovarian cancer is the most lethal gynecologic malignancy worldwide. Among its subtypes, ovarian clear cell carcinoma (OCCC) is characterized by its intrinsic chemoresistance, poor prognosis, and lack of effective therapies. To date, only ARID1A mutant OCCC has shown modest sensitivity to PARP inhibitors, highlighting the urgent need for novel therapeutic targets. Here, we identified BMAL2, a circadian transcription as a critical DNA integrity regulator in OCCC cells. BMAL2 depletion downregulated RAD51, impaired homologous recombination-mediated DNA repair thereby inhibited cell survival and tumor growth. To pharmacologically target BMAL2, we performed structure-based virtual screening and identified GW-833972A as a small-molecule inhibitor that effectively bound and degraded BMAL2 protein. Mechanistically, GW-833972A mediated BMAL2 degradation impaired DNA repair and suppressed tumor growth in vivo . Collectively, these findings reveal the critical oncogenic role of BMAL2 in OCCC and demonstrate that BMAL2 inhibition offers a promising therapeutic strategy for this chemoresistant cancer.
利益披露 Disclosure
G. Tan, None..
P. Lin, None..
L. Cheng, None..
W. Hwang-Verslues, None.