The cytoplasmic deacetylase HDAC6 is required for efficient oncogenic tumorigenesis

Yi Shan Lee, Kian Huat Lim, Xing Guo, Yoshiharu Kawaguchi, Yasheng Gao, Tomasa Barrientos, Peter Ordentlich, Xiao Fan Wang, Christopher M. Counter, Tso Pang Yao

Research output: Contribution to journalArticlepeer-review

201 Scopus citations

Abstract

Histone deacetylase inhibitors (HDACI) are promising antitumor agents. Although transcriptional deregulation is thought to be the main mechanism underlying their therapeutic effects, the exact mechanism and targets by which HDACIs achieve their antitumor effects remain poorly understood. It is not known whether any of the HDAC members support robust tumor growth. In this report, we show that HDAC6, a cytoplasmic-localized and cytoskeleton-associated deacetylase, is required for efficient oncogenic transformation and tumor formation. We found that HDAC6 expression is induced upon oncogenic Ras transformation. Fibroblasts deficient in HDAC6 are more resistant to both oncogenic Ras and ErbB2-dependent transformation, indicating a critical role for HDAC6 in oncogene-induced transformation. Supporting this hypothesis, inactivation of HDAC6 in several cancer cell lines reduces anchorage-independent growth and the ability to form tumors in mice. The loss of anchorage- independent growth is associated with increased anoikis and defects in AKT and extracellular signal-regulated kinase activation upon loss of adhesion. Lastly, HDAC6-null mice are more resistant to chemical carcinogen-induced skin tumors. Our results provide the first experimental evidence that a specific HDAC member is required for efficient oncogenic transformation and indicate that HDAC6 is an important component underlying the antitumor effects of HDACIs.

Original languageEnglish
Pages (from-to)7561-7569
Number of pages9
JournalCancer research
Volume68
Issue number18
DOIs
StatePublished - Sep 15 2008

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