Abstract
BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, with high incidence and mortality rates, and the number of cases is expected to increase by 2030. Understanding the molecular mechanisms of HCC and identifying new therapeutic targets and biomarkers for HCC are crucial. METHODS: In this study, we examined adaptor-related protein complex 5 subunit ζ1 (AP5Z1) expression in liver cancer and nearby noncancerous tissues to explore its effects on HCC cell growth, death, and autophagy. The functional and molecular mechanisms of AP5Z1 were studied using clinical sample analysis, Western blot (WB), immunohistochemistry (IHC), quantitative reverse-transcription polymerase chain reaction (qRT‒PCR), coimmunoprecipitation (Co-IP), cell proliferation assays, flow cytometry (FCM), autophagy assays, electron microscopy, mass spectrometry (MS), transcriptome analysis, and animal model experiments. RESULTS: AP5Z1 expression was notably higher in HCC tissues than in normal tissues and was linked to a poor prognosis. The results of both in vitro and in vivo studies revealed that AP5Z1 promoted HCC cell growth and reduced apoptosis. In addition, AP5Z1 regulates cellular autophagy by ubiquitinating the phosphatase and tensin homolog (PTEN) protein and modulating the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway. CONCLUSIONS: AP5Z1 influences autophagy and apoptosis in HCC cells by interacting with PTEN to modulate the PI3K/Akt/mTOR pathway. This gene might promote PTEN ubiquitination and degradation by recruiting tripartite motif-containing protein 21 (TRIM21), making it a potential biomarker for diagnosing and predicting the outcome of HCC as well as a target for new treatment strategies.