2. Academic Validation
  3. KLF5 Promotes Tumor Progression and Parp Inhibitor Resistance in Ovarian Cancer

KLF5 Promotes Tumor Progression and Parp Inhibitor Resistance in Ovarian Cancer

  • Adv Sci (Weinh). 2023 Sep 13;e2304638. doi: 10.1002/advs.202304638.
Yong Wu 1 2,  Siyu Chen 1 2,  Yang Shao 1 2,  Ying Su 1 2,  Qin Li 1 2,  Jiangchun Wu 1,  Jun Zhu 1,  Hao Wen 1,  Yan Huang 1,  Zhong Zheng 1,  Xiaojun Chen 1,  Xingzhu Ju 1,  Shenglin Huang 1 2,  Xiaohua Wu 1 2,  Zhixiang Hu 1 2
Affiliations

Affiliations

  • 1 Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
PMID: 37702443 DOI: 10.1002/advs.202304638
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.

Keywords

KLF5; PARPi resistance; RAD51; homologous recombination repair; ovarian cancer; super-enhancer.

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