This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Lee, Y.-S. Articles by Yao, T.-P. PubMed PubMed Citation Articles by Lee, Y.-S. Articles by Yao, T.-P.

The Cytoplasmic Deacetylase HDAC6 Is Required for Efficient Oncogenic Tumorigenesis

¹ Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina and ² Syndax Pharmaceuticals, Waltham, Massachusetts

Requests for reprints: Tso-Pang Yao, Department of Pharmacology and Cancer Biology, Box 3813, Duke University Medical Center, Durham, NC 27710. Phone: 919-613-8654; Fax. 919-668-3954; E-mail: yao00001{at}mc.duke.edu.

Key Words: HDAC6 • deacetylation • anoikis • transformation • HDACI

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. [Cancer Res 2008;68(18):7561–9]