HDAC1 Inactivation Induces Mitotic Defect and Caspase-Independent Autophagic Cell Death in Liver Cancer

Abstract

Histone deacetylases (HDACs) are known to play a central role in the regulation of several cellular properties interlinked with the development and progression of cancer. Recently, HDAC1 has been reported to be overexpressed in hepatocellular carcinoma (HCC), but its biological roles in hepatocarcinogenesis remain to be elucidated. In this study, we demonstrated overexpression of HDAC1 in a subset of human HCCs and liver cancer cell lines. HDAC1 inactivation resulted in regression of tumor cell growth and activation of caspase-independent autophagic cell death, via LC3B-II activation pathway in Hep3B cells. In cell cycle regulation, HDAC1 inactivation selectively induced both p21WAF1/Cip1 and p27Kip1 expressions, and simultaneously suppressed the expression of cyclin D1 and CDK2. Consequently, HDAC1 inactivation led to the hypophosphorylation of pRb in G1/S transition, and thereby inactivated E2F/DP1 transcription activity. In addition, we demonstrated that HDAC1 suppresses p21WAF1/Cip1 transcriptional activity through Sp1-binding sites in the p21WAF1/Cip1 promoter. Furthermore, sustained suppression of HDAC1 attenuated in vitro colony formation and in vivo tumor growth in a mouse xenograft model. Taken together, we suggest the aberrant regulation of HDAC1 in HCC and its epigenetic regulation of gene transcription of autophagy and cell cycle components. Overexpression of HDAC1 may play a pivotal role through the systemic regulation of mitotic effectors in the development of HCC, providing a particularly relevant potential target in cancer therapy.

Targeting Histone Deacetylases in Diseases: Where Are We?

“…HDAC1 overexpression has been found in gastric (35,155), breast (115), pancreatic (70,262), hepatocellular (58,244), lung (186), and prostate (200) malignancies, and overexpression levels correlate with prognosis and survival. High expression levels of HDAC1, 2, and 3 are associated with renal cancer (63) and Hodgkin's lymphoma (1).…”

Genetics and epigenetics of liver cancer

“…promoter [31]. HDAC4 also suppresses the promoter activity of miR200a and its expression and interacts with Sp1 in the miR-200a promoter to attenuate histone H3 acetylation levels.…”

Exploration of the binding pocket of histone deacetylases: the design of potent and isoform-selective inhibitors

“…Aberrant expressions of HDACs in diverse cancer cell lines and tumor tissues have been reported (Bolden et al, 2006). HDAC1 was overexpressed in prostate (Halkidou et al, 2004) and breast cancers (Zhang et al, 2005), hepatocellular carcinoma via systemic regulation of mitotic effectors (Xie et al, 2012), and impaired spermatogenesis and testicular cancer (Cacan et al, 2014). Despite functional redundancy between HDACs 1 and 2, HDAC2 was shown to be independently implicated in various types of human cancers.…”