The PRMT5 inhibitor C9 mitigates hypoxia‐induced carboplatin resistance in lung cancer by inducing autophagy

Abstract

Hypoxia, a common feature of solid tumors, can promote chemoresistance in cancer cells. PRMT5 mediates various cellular processes involved in cancer development and progression. However, the role of PRMT5 in hypoxia‐induced chemoresistance is unclear. In this study, hypoxia upregulated PRMT5 expression in lung cancer cells. Additionally, PRMT5 overexpression promoted cancer cell resistance to carboplatin. In carboplatin‐resistant cancer cells, PRMT5 overexpression promoted the methylation of ULK1, a critical regulator of autophagy. ULK1 hypermethylation leads to the upregulation of autophagy, which can improve the survival of cancer cells under hypoxic conditions. Furthermore, this study demonstrated that the PRMT5 inhibitor C9 significantly enhanced the sensitivity of lung cancer cells to carboplatin. These findings suggest that targeting PRMT5‐mediated autophagy with C9 can overcome hypoxia‐induced carboplatin resistance and improve the efficacy of chemotherapy in patients with cancer.

Inhibition of epigenetic and cell cycle-related targets in glioblastoma cell lines reveals that onametostat reduces proliferation and viability in both normoxic and hypoxic conditions

“…S3 – S5 ). This is in line with the reports on the elevated expression of PRMT5 52 , 53 and elevated activity of CDK4/6 54 , 55 under hypoxic conditions.…”

“…The absence of apoptotic effect of onametostat in all cell lines under normoxic conditions (Supplementary Fig. S8 ) also indirectly confirmed the cytostatic properties of the compound—although further studies should explore whether onametostat induces autophagy in GB, as autophagy has been shown to dictate sensitivity towards PRMT5 inhibition in other cancer types 53 , 80 .…”