肿瘤细胞的一个主要特征是表观遗传调控元件的异常激活，这些元件重塑了肿瘤转录组，并最终促进了癌症的发展和药物耐药性。然而，卵巢癌（OC）的致癌功能和机制仍然不清楚。在本研究中，鉴定了OC中异常激活的超级增强子（SE）调控元件，并发现SEs驱动转录因子KLF5在OC患者和聚合酶链反应酶抑制剂（PARPi）耐药患者中的相对特异表达。KLF5的表达与OC患者的预后不良相关，并能够在体外和体内推动肿瘤的进展。机械上讲，KLF5与EHF和ELF3形成转录复合物，并结合RAD51的启动子区域增强其转录，从而增强同源重组修复（HRR）途径。值得注意的是，亚洲烟酰胺羟酸盐（SAHA）和奥拉帕尼组合可显著抑制具有高KLF5的PARPi耐药OC细胞的肿瘤生长和转移。综上所述，发现了SEs驱动的KLF5是OC进展和PARPi耐药的关键调控因子，并确定了对于具有PARPi耐药和高KLF5的OC患者的潜在治疗策略。© 2023 The Authors. Wiley-VCH GmbH发表的Advanced Science。

One major characteristic of tumor cells is the aberrant activation of epigenetic regulatory elements, which remodel the tumor transcriptome and ultimately promote cancer progression and drug resistance. However, the oncogenic functions and mechanisms of ovarian cancer (OC) remain elusive. Here, super-enhancer (SE) regulatory elements that are aberrantly activated in OC are identified and it is found that SEs drive the relative specific expression of the transcription factor KLF5 in OC patients and poly(ADP-ribose) polymerase inhibitor (PARPi)-resistant patients. KLF5 expression is associated with poor outcomes in OC patients and can drive tumor progression in vitro and in vivo. Mechanistically, KLF5 forms a transcriptional complex with EHF and ELF3 and binds to the promoter region of RAD51 to enhance its transcription, strengthening the homologous recombination repair (HRR) pathway. Notably, the combination of suberoylanilide hydroxamic acid (SAHA) and olaparib significantly inhibits tumor growth and metastasis of PARPi-resistant OC cells with high KLF5. In conclusion, it is discovered that SEs-driven KLF5 is a key regulatory factor in OC progression and PARPi resistance; and potential therapeutic strategies for OC patients with PARPi resistance and high KLF5 are identified.© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.