HDAC2 promotes autophagy-associated HCC malignant progression by transcriptionally activating LAPTM4B

Abstract

Hepatocellular carcinoma (HCC) is a significant global health challenge. The activation of autophagy plays an essential role in promoting the proliferation and survival of cancer cells. However, the upstream regulatory network of autophagy and its mechanism of regulation in HCC remains unclear. This study demonstrated that histone deacetylase 2 (HDAC2) is a target for regulating autophagy in HCC, its expression is elevated in HCC tissues, and high HDAC2 expression is strongly related to dismal prognosis in individuals with HCC. Integrated in vitro and in vivo investigations verified that HDAC2 promotes autophagy and autophagy-related malignant progression in HCC. Mechanistically, HDAC2 specifically binds to the lysosome-associated protein transmembrane 4-β (LAPTM4B) promoter through four specific binding sites, enhancing its transcriptional activation and driving autophagy-related malignant progression in HCC. These findings confirm LAPTM4B as a new HDAC2 straight target gene. Additionally, the study found that HDAC2 expression is an independent predictor of HCC patients, according to multivariate Cox regression analysis of 105 human HCC samples. This study highlights the crucial role of the HDAC2-LAPTM4B axis in regulating autophagy in the malignant evolution of HCC and emphasizes the promise of HDAC2 as an avenue for preventing and arresting the malignant progression of HCC.