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.
Highlights
Hepatocellular carcinoma (HCC) is a primary malignancy of human liver and a major cause of morbidity and mortality
We recapitulated the expression of HDAC1 in a multi-step histopathological process, from low-grade dysplastic nodules (LGDNs) and high-grade dysplastic nodules (HGDNs) to primary HCC (Edmondson grades 1–3)
Our present results suggest that the transcriptional suppression of p21WAF1/Cip1 through HDAC1 binding on its promoter region is predominant in liver cancer cells
Summary
Hepatocellular carcinoma (HCC) is a primary malignancy of human liver and a major cause of morbidity and mortality. HDAC1 knockdown affected cell motility and invasion by regulating E-cadherin expression [13,14], and was shown to induce autophagy in Hela cells [15], and cellular senescence in human fibroblast cells and prostate cancer cells [16]. These molecular functions of HDAC1 were well documented in numerous previous results, the role of HDAC1 in hepatocarcinogenesis has not been elucidated
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