Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHFPC; West China Hospital, Sichuan University, Chengdu, 610041, China.
Department of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China.
Cell Death Dis. 2018 Mar 14;9(3):398. doi: 10.1038/s41419-018-0428-x.
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.
组蛋白去乙酰化酶 3（HDAC3）在细胞周期调控中发挥关键作用，在包括肝细胞癌（HCC）在内的各种癌症中经常异常表达，但人们对其在肝再生和肝癌细胞增殖中的作用知之甚少。使用诱导型肝细胞选择性 HDAC3 敲除小鼠，我们发现缺乏 HDAC3 可显著损害肝再生并阻止 G1 期进入的肝细胞增殖。HDAC3 失活强烈破坏了信号转导子和转录激活子 3（STAT3）级联反应。HDAC3 沉默削弱了细胞质中 ac-STAT3 到 p-STAT3 的转变，导致随后的 STAT3 信号中断。此外，高表达的 HDAC3 与 HCC 患者的肿瘤生长增加和预后不良进一步相关。抑制 HDAC3 的表达可降低肝癌细胞的生长并抑制异种移植肿瘤的生长。我们的研究结果表明，HDAC3 是肝再生和癌症中 STAT3 依赖性细胞增殖的重要调节剂。这些发现为肝生理病理过程中的 HDAC3-STAT3 通路提供了新的见解。
