Journal Article

Opposing roles of HDAC6 in liver regeneration and hepatocarcinogenesis

Phorl, Sophors, Lee, Joo‐Yong, Hoang, Thi Oanh, Tran, Trung Nghia, Lee, Chang Hoon, Nguyen, Le Minh Tri, Seo, Yuri, Lee, Woon Kyu, Memon, Azra

2022

Overview

Histone deacetylase 6 (HDAC6), a deacetylase of p53, has emerged as a privileged inhibitory target for cancer therapy because of its deacetylating activity for p53 at K120 and K373/382. However, intricate roles of HDAC6 in hepatocellular carcinogenesis have been suggested by recent evidence, namely that HDAC6 ablation suppresses innate immunity, which plays critical roles in tumor immunosurveillance and antitumor immune responses. Therefore, it is valuable to determine whether HDAC6 ablation inhibits hepatocellular carcinogenesis using in vivo animal models. Here, we firstly showed that HDAC6 ablation increased K320 acetylation of p53, known as pro‐survival acetylation, in all tested animal models but did not always increase K120 and K373/382 acetylation of p53, known as pro‐apoptotic acetylation. HDAC6 ablation induced cellular senescence in primary MEFs and inhibited cell proliferation in HepG2 cells and liver regeneration after two‐thirds partial hepatectomy. However, the genetic ablation of HDAC6 did not inhibit hepatocarcinogenesis, but instead slightly enhanced it in two independent mouse models (DEN + HFD and DEN + TAA). Notably, HDAC6 ablation significantly promoted hepatocarcinogenesis in a multiple DEN treatment hepatocellular carcinoma (HCC) mouse model, mimicking chronic DNA damage in the liver, which correlated with hyperacetylation at K320 of p53 and a decrease in inflammatory cytokines and chemokines. Our data from three independent in vivo animal HCC models emphasize the importance of the complex roles of HDAC6 ablation in hepatocellular carcinogenesis, highlighting its immunosuppressive effects. We provide the first evidence that HDAC6 is a p53 deacetylase at K320, which is especially important for cancer cell survival in chronic DNA damage conditions. Contrary to the general assumption that HDAC6 inhibition leads to hyperacetylation of p53 at K120, resulting in tumor suppression, our findings from in vivo animal HCC modelsemphasize the importance of the opposing roles of HDAC6 ablation in hepatocellular carcinogenesis by highlighting the K320 acetylation of p53 and immunosuppressive effects.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Ablation / Acetylation / Animal models / Antitumor activity / Apoptosis / Carcinogenesis / Cell cycle / Cell growth / Cell proliferation / Chemokines / Cytokines / DNA damage / HDAC6 / Hepatectomy / hepatocellular carcinogenesis / Hepatocellular carcinoma / Hepatocytes / Histone deacetylase / Immune response / Immunosurveillance / Inflammation / Innate immunity / Liver / Liver cancer / Liver diseases / Original / p53 / p53 Protein / Physiology / Polyploidy / Proteins / Roles / Senescence / Tumors