EZH2 promotes chemoresistance in colorectal cancer by inhibiting autophagy through NRP1 suppression.

Colorectal cancer (CRC) is characterized by aggressive tumor growth and chemoresistance, with Enhancer of zeste homolog 2 (EZH2) serving a pivotal role in these processes. However, the mechanisms by which it drives tumor proliferation and therapeutic resistance through autophagy regulation remain unclear. Here, we demonstrated that EZH2 expression is elevated in CRC tissues and cell lines, correlating with chemoresistance and diagnostic potential (Area Under the Curve, AUC = 0.968). EZH2 knockdown markedly reduced CRC cell proliferation, while its overexpression promoted tumor growth and increased resistance to irinotecan. Mechanistically, EZH2 suppressed autophagy in CRC cells, a process linked to chemosensitivity, by directly regulating LC3bI/II expression. Notably, EZH2 enhanced the Neuropilin-1 (NRP1) level by binding to the NRP1 promoter, thereby promoting tumor proliferation and irinotecan resistance through autophagy inhibition. NRP1 depletion partially reversed these effects, underscoring the crucial role of the EZH2-NRP1 axis in CRC. Our findings highlight that targeting the EZH2-NRP1 interaction could represent a novel therapeutic approach to overcoming chemoresistance in CRC.