Antitumor effects in hepatocarcinoma of isoform-selective inhibition of HDAC2

Yun Han Lee, Daekwan Seo, Kyung Ju Choi, Jesper B. Andersen, Min Ah Won, Mitsuteru Kitade, Luis E. Gómez-Quiroz, Adam D. Judge, Jens U. Marquardt, Chiara Raggi, Elizabeth A. Conner, Ian MacLachlan, Valentina M. Factor, Snorri S. Thorgeirsson

Research output: Contribution to journalArticle

Abstract

Histone deacetylase 2 (HDAC2) is a chromatin modifier involved in epigenetic regulation of cell cycle, apoptosis, and differentiation that is upregulated commonly in human hepatocellular carcinoma (HCC). In this study, we show that specific targeting of this HDAC isoform is sufficient to inhibit HCC progression. siRNA-mediated silencing of HDAC inhibited HCC cell growth by blocking cell-cycle progression and inducing apoptosis. These effects were associated with deregulation of HDAC-regulated genes that control cell cycle, apoptosis, and lipid metabolism, specifically, by upregulation of p27 and acetylated p53 and by downregulation of CDK6 and BCL2. We found that HDAC2 silencing in HCC cells also strongly inhibited PPARγ signaling and other regulators of glycolysis (ChREBPα and GLUT4) and lipogenesis (SREBP1C and FAS), eliciting a marked decrease in fat accumulation. Notably, systemic delivery of HDAC2 siRNA encapsulated in lipid nanoparticles was sufficient to blunt the growth of human HCC in a murine xenograft model. Our findings offer preclinical proof-of-concept for HDAC2 blockade as a systemic therapy for liver cancer.

Original languageEnglish
Pages (from-to)4752-4761
Number of pages10
JournalCancer Research
Volume74
Issue number17
DOIs
Publication statusPublished - Sep 1 2014

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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    Lee, Y. H., Seo, D., Choi, K. J., Andersen, J. B., Won, M. A., Kitade, M., Gómez-Quiroz, L. E., Judge, A. D., Marquardt, J. U., Raggi, C., Conner, E. A., MacLachlan, I., Factor, V. M., & Thorgeirsson, S. S. (2014). Antitumor effects in hepatocarcinoma of isoform-selective inhibition of HDAC2. Cancer Research, 74(17), 4752-4761. https://doi.org/10.1158/0008-5472.CAN-13-3531