KLF5 Promotes Tumor Progression and Parp Inhibitor Resistance in Ovarian Cancer

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.

Automated summary

This study identifies super-enhancer regulatory elements that are aberrantly activated in ovarian cancer (OC) and shows that they drive the expression of the transcription factor KLF5. KLF5 is associated with poor outcomes in OC patients and can promote tumor progression by enhancing the homologous recombination repair pathway and increasing PARP inhibitor resistance. The combination of SAHA and olaparib is found to significantly inhibit tumor growth and metastasis in PARP inhibitor-resistant OC cells with high KLF5 expression.