The endosomal system maintains cellular homeostasis by coordinating multiple vesicular trafficking events, and the retromer complex plays a critical role in endosomal cargo recognition and sorting. Here, we demonstrate an essential role for the small GTPase RAB21 in regulating retromer-mediated recycling of the glucose transporter SLC2A1/GLUT1 and macroautophagy/autophagy. RAB21 depletion mis-sorts SLC2A1 to lysosomes and affects glucose uptake, thereby activating the AMPK-ULK1 pathway to increase autophagic flux. RAB21 depletion also increases lysosome function. Notably, RAB21 depletion does not overtly affect retrograde transport of IGF2R/CI-M6PR or WLS from endosomes to the trans-Golgi network. We speculate that RAB21 regulates fission of retromer-decorated endosomal tubules, as RAB21 depletion causes accumulation of the SNX27-containing retromer complex on enlarged endosomes at the perinuclear region. Functionally, RAB21 depletion sensitizes cancer cells to energy stress and inhibits tumor growth in vivo, suggesting an oncogenic role for RAB21. Overall, our study illuminates the role of RAB21 in regulating endosomal dynamics and maintaining cellular energy homeostasis and suggests RAB21 as a potential metabolic target for cancer therapy.

Loss of tumor suppressor gene p16 expression via promoter methylation has been reported in hepatocellular carcinoma (HCC). This meta-analysis was conducted to evaluate the correlation between p16 methylation and HCC. Additionally, we also analyzed the potential prognostic role of p16 methylation, expression or alteration-associated HCC. Online databases based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline were performed to analyze the role of p16 gene in HCC. The combined odds ratios (ORs) or hazard ratios (HRs) and their 95% confidence intervals (95% CIs) were summarized. Final 3105 HCCs and 808 non-tumor controls (chronic hepatitis and liver cirrhosis) were performed in this meta-analysis. p16 promoter methylation in HCC was significantly higher than in chronic hepatitis and chronic hepatitis in tissue and blood samples. In addition, p16 promoter methylation was notably higher in patients >50 years’ old than in patients aged <50 years, and it was higher in hepatitis B virus (HBV) or hepatitis C virus (HCV)-positive HCC than in hepatic viruses-negative HCC. However, p16 promoter methylation was not correlated with sex, cirrhosis, tumor differentiation, clinical stage. No association was found between p16 methylation or alteration and the prognosis of patients with HCC in overall survival (OS) and disease-free survival (DFS). Although p16 expression was significantly correlated with a poor prognosis in OS and DFS (P < .05) Our results indicate that p16 methylation was linked to the development, age, HBV, and HCV infection of HCC. p16 methylation or alteration was not associated with the prognosis, but p16 expression was linked to a poor survival.

Wnt signalling pathways play pivotal roles in development, homeostasis and human diseases, and are tightly regulated. We previously identified Tiki as a novel family of Wnt inhibitory proteases. Tiki proteins were predicted as type I transmembrane proteins and can act in both Wnt‐producing and Wnt‐responsive cells. Here, we characterize Tiki proteins as glycosylphosphatidylinositol (GPI)‐anchored proteases. TIKI1/2 proteins are enriched on the detergent‐resistant membrane microdomains and can be released from the plasma membrane by GPI‐specific glycerophosphodiesterases GDE3 and GDE6, but not by GDE2. The GPI anchor determines the cellular localization of Tiki proteins and their regulation by GDEs, but not their inhibitory activity on Wnt signalling. Our study uncovered novel characteristics and potential regulations of the Tiki family proteases.