YWHAH‑driven autophagy via MAPK/ERK signaling enhances CRC cell migration and invasion

The present study investigated the role of YWHAH in colorectal cancer (CRC) progression, focusing on its regulation of autophagy via the MAPK/ERK signaling pathway and subsequent effects on cell migration and invasion. Clinical sample analysis revealed that YWHAH was highly expressed in CRC tissues, associating with poor differentiation, advanced TNM stage, lymph node metastasis, vascular invasion and unfavorable prognosis. In vitro experiments showed that YWHAH overexpression promoted proliferation, and epithelial‑mesenchymal transition of CRC cells, while inhibiting apoptosis. Conversely, YWHAH knockdown exerted opposite effects. Autophagy assays demonstrated that YWHAH knockdown enhanced autophagy by upregulating autophagy related 7 and LC3II/I and downregulating P62, whereas overexpression suppressed autophagy. Mechanistically, YWHAH negatively regulated the MAPK/ERK pathway [reducing phosphorylated (p)‑ERK1/2 and p‑ELK‑1 levels] to inhibit autophagy. The ERK inhibitor PD98059 reversed autophagy activation by YWHAH knockdown, while the ERK agonist U‑46619 reversed autophagy suppression by YWHAH overexpression. Additionally, the autophagy inhibitor 3‑methyladenine abrogated the inhibitory effects of YWHAH knockdown on migration and invasion, and the autophagy inducer rapamycin reversed the promoting effects of YWHAH overexpression. In vivo, nude mouse xenograft models confirmed that YWHAH inhibited autophagy via the MAPK/ERK pathway to accelerate tumor growth. These findings underscore the role of YWHAH as a critical regulator of CRC progression and suggest it as a potential therapeutic target. Interventions targeting YWHAH or its downstream factors may provide innovative approaches for treating CRC, particularly by modulating autophagy to inhibit tumor growth and metastasis.