KCMF1 regulates HRI ubiquitination to inhibit the integrated stress response in ovarian cancer
This study aimed to investigate the biological functions and underlying mechanisms of potassium channel modulatory factor 1 (KCMF1) in ovarian cancer (OC). KCMF1 expression in OC was analyzed using single-cell sequencing, quantitative real-time reverse transcription polymerase chain reaction, immunohistochemistry, and western blot analysis. The effects of KCMF1 on OC progression were evaluated in cell lines and a xenograft mouse model. The effect of KCMF1 on the integrated stress response (ISR) was evaluated by assessing heme-regulated inhibitor (HRI) ubiquitination using Ni-NTA pull-down assays, immunohistochemistry, and western blotting. KCMF1 was highly expressed in OC epithelial cells and was associated with poor prognosis in patients with OC. Overexpression of KCMF1 promoted OC cell proliferation, migration, and invasion and inhibited cell apoptosis. On the other hand, KCMF1 knockdown produced the opposite results and inhibited tumor growth. Knockdown of KCMF1 reduced HRI ubiquitination and promoted the phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (eIF2α), and the expression of activating transcription factor (ATF)4, ATF3, and sestrin 2 (SESN2), while KCMF1 overexpression produced the opposite results. Additionally, an ISR inhibitor reversed the effects of KCMF1 knockdown on OC cell proliferation, migration, and invasion. Plantainoside D was identified as a novel KCMF1 inhibitor that exhibited potent antitumor activity in OC. Overall, KCMF1 regulates HRI ubiquitination to inhibit ISR, thereby promoting tumor growth and progression in OC.