Histone deacetylase 3 promotes liver regeneration and liver cancer cells proliferation through signal transducer and activator of transcription 3 signaling pathway

Abstract

Histone deacetylase 3 (HDAC3) plays pivotal roles in cell cycle regulation and is often aberrantly expressed in various cancers including hepatocellular carcinoma (HCC), but little is known about its role in liver regeneration and liver cancer cells proliferation. Using an inducible hepatocyte-selective HDAC3 knockout mouse, we find that lack of HDAC3 dramatically impaired liver regeneration and blocked hepatocyte proliferation in the G1 phase entry. HDAC3 inactivation robustly disrupted the signal transducer and activator of transcription 3 (STAT3) cascade. HDAC3 silencing impaired the ac-STAT3-to-p-STAT3 transition in the cytoplasm, leading to the subsequent breakdown of STAT3 signaling. Furthermore, overexpressed HDAC3 was further associated with increased tumor growth and a poor prognosis in HCC patients. Inhibition of HDAC3 expression reduced liver cancer cells growth and inhibited xenograft tumor growth. Our results suggest that HDAC3 is an important regulator of STAT3-dependent cell proliferation in liver regeneration and cancer. These findings provide novel insights into the HDAC3–STAT3 pathway in liver pathophysiological processes.

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

“…Class I-specific HDACi 4SC-202 globally increases both of H3K27ac and H3K4me3 levels around the TSS of genes, but notably decreases occupancy at proximal regions of TSS of genes such as SMAD family member 6 (SMAD6) and E2F transcription factor 8 (E2F8), which are associated with enhancer deactivation (Mishra et al, 2017). Panobinostat and Jamaladdin et al, 2014Heideman et al, 2013Lin et al, 2019Haberland et al, 2009Boucheron et al, 2014Preglej et al, 2020Montgomery et al, 2007Moresi et al, 2012;Dovey et al, Montgomery et al, 2008Lu et al, 2018Ho et al, 2020Bhaskara et al, 2008Bhaskara et al, 2010;Jiang and Hsieh, 2014Ji et al, 2019Hsu et al, 2015Phelps et al, 2016 Chen Impairs genome stability; embryonic lethality Vaquero et al, 2007;Wang et al, 2008 Represses angiogenesis Potente et al, 2007;Dioum et al, 2009;Lim et al, 2010 Impairs nicotinamide mononucleotide (NMN)-induced amelioration of liver fibrosis and NMN-dependent telomere integrity in premature aging mice Amano et al, 2019 Causes methionine restriction-induced lethality in mouse ESC Tang S. et al, 2017 Impairs myeloid-derived suppressor cells (MDSC) differentiation by disturbing glycolytic pathway Liu et al, 2014 Impairs various DNA repair Cohen et al, 2004;Yuan et al, 2007;Ming et al, 2010;Meng et al, 2020 Inhibits autophagy in MEFs Lee et al, 2008 Causes differentiation defects of mice ESC Tang Induces abnormal mitochondrial physiology, oxidative stress and genomic instability Kim et al, 2010 R...…”

Fine-scale visualizing the hierarchical structure of mouse biliary tree with fluorescence microscopy method

“…Liver samples were fixed in 10% neutral-buffered formalin for 48 h, and embedded in paraffin. For this purpose, the IF staining of glutamine synthetase (GS, Abcam, Cat #ab49873), β-catenin (Abcam, Cat #ab32572), and CK19 (Abcam, Cat #ab133496) and IHC staining of SOX9 (Abcam, Cat #ab185966) and CK19 were carried out as described previously [13]. The images were captured with fluorescence microscope (Leica DM4000B) and light microscopy (Olympus DP Controller 70), respectively.…”

<p>RGFP966 Suppresses Tumor Growth and Migration Through Inhibition of EGFR Expression in Hepatocellular Carcinoma Cells in vitro</p>

“…14 Copy number gain of HDAC3 occurs in HCC and overexpressed HDAC3 is associated with increased tumor growth and a poor prognosis in HCC patients. 8,15 Further, HDAC3 is an important regulator of STAT3-dependent cell proliferation in and liver cancer cells proliferation. 15 Moreover, HDAC3 plays a critical role in regulating self-renewal of liver cancer stem cells and liver regeneration.…”

“…8,15 Further, HDAC3 is an important regulator of STAT3-dependent cell proliferation in and liver cancer cells proliferation. 15 Moreover, HDAC3 plays a critical role in regulating self-renewal of liver cancer stem cells and liver regeneration. 15,16 In addition, HDAC3 may be served as a candidate biomarker for predicting the recurrence of hepatitis B virus-associated HCC following liver transplantation and a potential therapeutic target.…”

“…15 Moreover, HDAC3 plays a critical role in regulating self-renewal of liver cancer stem cells and liver regeneration. 15,16 In addition, HDAC3 may be served as a candidate biomarker for predicting the recurrence of hepatitis B virus-associated HCC following liver transplantation and a potential therapeutic target. 17 Consequently, HDAC3 suppression by RGFP966 may be a potential medical-therapeutic approach for HCC.…”