title: HDAC6 and SIRT2 regulate the acetylation state and oncogenic activity of mutant K-RAS.
abstract: Activating point mutations in K-RAS are extremely common in cancers of the lung, colon, and pancreas and are highly predictive of poor therapeutic response. One potential strategy for overcoming the deleterious effects of mutant K-RAS is to alter its posttranslational modification. Although therapies targeting farnesylation have been explored, and have ultimately failed, the therapeutic potential of targeting other modifications remains to be seen. Recently, it was shown that acetylation of lysine 104 attenuates K-RAS transforming activity by interfering with GEF-induced nucleotide exchange. Here, the deacetylases HDAC6 and SIRT2 were shown to regulate the acetylation state of K-RAS in cancer cells. By extension, inhibition of either of these enzymes has a dramatic impact on the growth properties of cancer cells expressing activation mutants of K-RAS. These results suggest that therapeutic targeting of HDAC6 and/or SIRT2 may represent a new way to treat cancers expressing mutant forms of K-RAS.
  
  
  CONCLUSIONS
  This study suggests that altering K-RAS acetylation is a feasible approach to limiting tumorigenic potential.
authors.affiliation: Molecular Pathology Unit, Center for Cancer Research, and Center for Systems Biology, Massachusetts General Hospital, 149 13 Street, Charlestown, MA 02129. khaigis@partners.org.
authors.forename: Moon Hee
authors.initials: MH
authors.lastname: Yang
authors.forename: Gaelle
authors.initials: G
authors.lastname: Laurent
authors.forename: Alexandra S
authors.initials: AS
authors.lastname: Bause
authors.forename: Robert
authors.initials: R
authors.lastname: Spang
authors.forename: Natalie
authors.initials: N
authors.lastname: German
authors.forename: Marcia C
authors.initials: MC
authors.lastname: Haigis
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Haigis
mesh_terms: D000107:Acetylation; D000818:Animals; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C474199:SIRT2 protein, human; D056565:Sirtuin 2; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins