TRAF6 regulates autophagy and apoptosis of melanoma cells through c-Jun/ATG16L2 signaling pathway.

Autophagy and apoptosis are essential processes that participate in cell death and maintain cellular homeostasis. Dysregulation of these biological processes results in the development of diseases, including cancers. Therefore, targeting the interaction between apoptosis and autophagy offers a potential strategy for cancer therapy. Melanoma is the most lethal skin cancer. We previously found that tumor necrosis factor receptor-associated factor 6 (TRAF6) is overexpressed in melanoma and benefits the malignant phenotype of melanoma cells. Additionally, TRAF6 promotes the activation of cancer-associated fibroblasts in melanoma. However, the role of TRAF6 in autophagy and apoptosis remains unclear. In this study, we found that knockdown of TRAF6 induced both apoptosis and autophagy in melanoma cells. Transcriptomic data and real-time PCR analysis demonstrated reduced expression of autophagy related 16 like 2 (ATG16L2) in TRAF6-deficient melanoma cells. ATG16L2 knockdown resulted in increased autophagy and apoptosis. Mechanism studies confirmed that TRAF6 regulated ATG16L2 expression through c-Jun. Importantly, targeting TRAF6 with cinchonine, a TRAF6 inhibitor, effectively suppressed the growth of melanoma cells by inducing autophagy and apoptosis through the TRAF6/c-Jun/ATG16L2 signaling pathway. These findings highlight the pivotal role of TRAF6 in regulating autophagy and apoptosis in melanoma, emphasizing its significance as a novel therapeutic target for melanoma treatment.

Over-expressed RHEB promotes the progression of pancreatic adenocarcinoma.

AIMS: Mammalian/mechanistic target of rapamycin (mTOR) is essential in the progression of pancreatic adenocarcinoma (PAAD). But the role of Ras homolog enriched in brain (RHEB), a key activator of mTORC1, is unclear in this disease. This work aims to clarify the function of RHEB in PAAD. MATERIALS AND METHODS: A pan-cancer analysis of RHEB was conducted by using data from several public available databases. Immunohistochemical (IHC) staining on a tissue microarray was used to validate the expression of RHEB in PAAD. In vitro experiments were conducted to explore the function of RHEB in the disease. An integrated bioinformatics tools were used to understand the mechanism of RHEB and construct a RHEB-related prognostic signature. KEY FINDINGS: RHEB was significantly overexpressed in PAAD and high expression of the gene was associated with poor prognosis. RHEB promoted proliferation, migration and invasion of pancreatic cancer cells. Gene set enrichment analysis (GSEA) showed that RHEB participated in cell cycle progression and WNT signaling pathway. A RHEB-related prognostic signature was developed, and PAAD patients with high risk score had a significantly shorter overall survival. SIGNIFICANCE: RHEB was up-regulated in PAAD and might be a useful therapeutic target.