KLF5 Promotes Tumor Progression and Parp Inhibitor Resistance in Ovarian Cancer.
KLF5 Promotes Tumor Progression and Parp Inhibitor Resistance in Ovarian Cancer.
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KLF5促进卵巢癌肿瘤进展和Parp抑制剂耐药性
DOI：
10.1002/advs.202304638
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发表时间：
2023-11
期刊：
影响因子：
15.1
通讯作者：
Hu, Zhixiang
中科院分区：
文献类型：
--
作者：
Wu, Yong;Chen, Siyu;Shao, Yang;Su, Ying;Li, Qin;Wu, Jiangchun;Zhu, Jun;Wen, Hao;Huang, Yan;Zheng, Zhong;Chen, Xiaojun;Ju, Xingzhu;Huang, Shenglin;Wu, Xiaohua;Hu, Zhixiang
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，表观遗传调控元件重塑肿瘤转录组并最终促进癌症进展和耐药性。然而，卵巢癌（OC）的致癌功能和机制仍然难以捉摸。在这里，确定了在OC中异常激活的超级增强子（SE）调节元件，并发现SE驱动OC患者和聚（ADP-核糖）聚合酶抑制剂（PARPi）耐药患者中转录因子KLF 5的相对特异性表达。KLF 5表达与OC患者的不良结局相关，并可在体外和体内推动肿瘤进展。KLF 5与EHF和ELF 3形成转录复合物，并与RAD 51的启动子区域结合以增强其转录，从而加强同源重组修复（HRR）途径。值得注意的是，辛二酰苯胺异羟肟酸（SAHA）和奥拉帕尼的组合显著抑制具有高KLF 5的PARPi抗性OC细胞的肿瘤生长和转移。总之，发现SE驱动的KLF 5是OC进展和PARPi耐药的关键调节因子;并确定了PARPi耐药和高KLF 5的OC患者的潜在治疗策略。这项研究描绘了卵巢癌（OC）中异常激活的超级增强子调控元件的景观，并确定了两个调节Kruppel样因子5（KLF 5）转录的超级增强子，导致KLF 5自我转录调节。KLF 5与EHF和ELF 3形成转录复合物，重塑RAD 51转录，加强OC细胞中的同源重组修复途径，并最终促进OC进展和PARPi抗性。
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. This study depicts the landscape of abnormally activated super‐enhancer regulatory elements in ovarian cancer (OC) and identifies two super‐enhancers that regulate Kruppel‐like factor 5 (KLF5) transcription, resulting in KLF5 self‐transcriptional regulation. KLF5 forms a transcription complex with EHF and ELF3, remodels RAD51 transcription, strengthens the homologous recombination repair pathway in OC cells, and ultimately promotes OC progression and PARPi resistance.
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DOI：
10.1186/s13046-022-02570-4
发表时间：
2022-12-21
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
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作者：
通讯作者：
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PARP-1 高表达预示急性髓系白血病生存率较差，PARP-1 抑制剂和 SAHA-苯达莫司汀混合抑制剂联合治疗可协同增强抗肿瘤作用。
影响因子：
11.1
作者：
Li X;Li C;Jin J;Wang J;Huang J;Ma Z;Huang X;He X;Zhou Y;Xu Y;Yu M;Huang S;Yan X;Li F;Pan J;Wang Y;Yu Y;Jin J
通讯作者：
Jin J
FUS/circEZH2/KLF5/反馈环路通过增强上皮间质转化促进CXCR4诱导的乳腺癌肝转移
影响因子：
37.3
作者：
Liu, Peng;Wang, Zehao;Ou, Xueqi;Wu, Peng;Zhang, Yue;Wu, Song;Xiao, Xiangsheng;Li, Yuehua;Ye, Feng;Tang, Hailin
通讯作者：
Tang, Hailin
影响因子：
11.2
作者：
Longoni, Nicole;Sarti, Manuela;Carbone, Giuseppina M.
通讯作者：
Carbone, Giuseppina M.
影响因子：
158.5
作者：
Gonzalez-Martin, A.;Pothuri, B.;Monk, B. J.
通讯作者：
Monk, B. J.