The cytoplasmic deacetylase HDAC6 is required for efficient oncogenic tumorigenesis.
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.
Lee
Yi-Shan
YS
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA.
Lim
Kian-Huat
KH
Guo
Xing
X
Kawaguchi
Yoshiharu
Y
Gao
Yasheng
Y
Barrientos
Tomasa
T
Ordentlich
Peter
P
Wang
Xiao-Fan
XF
Counter
Christopher M
CM
Yao
Tso-Pang
TP
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D003593:Cytoplasm / Q000201:enzymology; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics
D056572:Histone Deacetylase Inhibitors; D034741:RNA, Small Interfering; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
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