癌症研究
肿瘤进展
PARP抑制剂
卵巢癌
聚ADP核糖聚合酶
生物
表观遗传学
转录因子
奥拉帕尼
转移
雷达51
癌症
聚合酶
化学
同源重组
基因
遗传学
作者
Yong Wu,Siyu Chen,Yang Shao,Ying Su,Qin Li,Jiawen Wu,Jun Zhu,Hao Wen,Yongwen Huang,Zhuo Zheng,Xiaojun Chen,Xingzhu Ju,Shenglin Huang,Xiaohua Wu,Zhixiang Hu
标识
DOI:10.1002/advs.202304638
摘要
Abstract 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.
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