PRMT1/PRMT5-Mediated Differential Arginine Methylation of CRIP1 Promotes the Recurrence of Small Cell Lung Cancer after Chemotherapy.

Abstract

Arginine methylation, a critical epigenetic modification, plays a vital role in tumor initiation and progression; however, the mechanism by which arginine methylation regulates tumor recurrence remains unclear. Here, we found the differential changes between arginine methyltransferase PRMT1 and PRMT5 in small cell lung cancer (SCLC) cells after cisplatin and etoposide treatment. PRMT5 increased at the early stage and then decreased at the later stage, while PRMT1 first decreased and then increased, which was regulated by an inflammation activated E3 ubiquitin ligase PELI1. Both PRMT5 and PRMT1 could modify the same substrate CRIP1. At the early stage, PRMT5-mediated CRIP1 R26/68 methylation activated the Wnt/β-catenin pathway to facilitate the acquisition of a stemness phenotype in senescent cells. At the later stage, PRMT1-mediated CRIP1 R16 methylation accelerated the proliferation of stem-like cells by suppressing the p38 pathway, thereby driving rapid recurrence of SCLC post-chemotherapy. Notably, combination therapy using PRMT5 inhibitor GSK3326595 along with cisplatin and etoposide significantly delayed the recurrence of SCLC. Our findings reveal the promoting effect of post-chemotherapy inflammation on tumor recurrence from an epigenetic perspective and provide a potential therapeutic strategy for SCLC treatment.