Oncogenic K-ras confers SAHA resistance by up-regulating HDAC6 and c-myc expression
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Qun Wang1,*, Rong Tan2,*, Xin Zhu3,*, Yi Zhang3, Zhiping Tan3, Bing Su1,2,4, Yu Li1
1Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China
2Xiangya Hospital, Central South University, Hunan, China
3Clinical Center for Gene Diagnosis and Therapy of The State Key Laboratory of Medical Genetics, Hunan, China
4Department of Immunobiology and The Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, USA
*These authors contributed equally to this work
Yu Li, e-mail: email@example.com
Bing Su, e-mail: firstname.lastname@example.org
Keywords: K-ras, HDAC inhibitor, SAHA resistance
Received: August 21, 2015 Accepted: January 19, 2016 Published: February 02, 2016
Histone deacetylase inhibitors (HDIs) represent a new class of anticancer drugs. Suberoylanilide hydroxamic acid (SAHA), the first HDI approved for the treatment of cutaneous T cell lymphoma (CTCL), is currently being tested in clinical trials for other cancers. However, SAHA has been ineffective against solid tumors in many clinical trials. A better understanding of molecular mechanisms of SAHA resistance may provide the basis for improved patient selection and the enhancement of clinical efficacy. Here we demonstrate that oncogenic K-ras contributes to SAHA resistance by upregulating HDAC6 and c-myc expression. We find that the high levels of HDAC6 expression are associated with activated K-ras mutant in colon cancer patients. And expressions of HDAC6 and c-myc are increased in fibroblasts transformed with activated K-ras. Surprisingly, we find that activated K-ras transformed cells are more resistant to SAHA inhibition on cell growth and anchorage-independent colony formation. We show that a K-ras inhibitor sensitizes K-ras mutated lung cancer cells to SAHA induced growth inhibition. We also find that mutant K-ras induces HDAC6 expression by a MAP kinase dependent pathway. Our study suggests that combined treatment with SAHA and K-ras inhibitors may represent an effective strategy to overcome SAHA resistance.
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