title: Oncogenic K-ras confers SAHA resistance by up-regulating HDAC6 and c-myc expression.
abstract: 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.
authors: Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors: Qun
authors: Q
authors: Wang
authors: Xiangya Hospital, Central South University, Hunan, China.
authors: Rong
authors: R
authors: Tan
authors: Clinical Center for Gene Diagnosis and Therapy of The State Key Laboratory of Medical Genetics, Hunan, China.
authors: Xin
authors: X
authors: Zhu
authors: Clinical Center for Gene Diagnosis and Therapy of The State Key Laboratory of Medical Genetics, Hunan, China.
authors: Yi
authors: Y
authors: Zhang
authors: Clinical Center for Gene Diagnosis and Therapy of The State Key Laboratory of Medical Genetics, Hunan, China.
authors: Zhiping
authors: Z
authors: Tan
authors: Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Xiangya Hospital, Central South University, Hunan, China.|Department of Immunobiology and The Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, USA.
authors: Bing
authors: B
authors: Su
authors: Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors: Yu
authors: Y
authors: Li
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002867:Chromones / Q000008:administration & dosage / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D009154:Mutation; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015854:Up-Regulation; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C117307:KRAS protein, human; C489427:MYC protein, human; D009025:Morpholines; D016271:Proto-Oncogene Proteins c-myc; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000077337:Vorinostat; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: HDAC inhibitor; K-ras; SAHA resistance