title: Oncogene Ras/phosphatidylinositol 3-kinase signaling targets histone H3 acetylation at lysine 56.
abstract: It is well established that the small GTPase Ras promotes tumor initiation by activating at least three different mediators: Raf, PI3K, and Ras-like (Ral) guanine nucleotide exchange factors. However, the exact mechanisms that underlie these different Ras signaling pathways, which are involved in tumor progression, remain to be elucidated. In this study, we report that the Ras-PI3K pathway, but not Raf or the Ral guanine nucleotide exchange factors, specifically targets the acetylation of H3 at lysine 56 (H3K56ac), thereby regulating tumor cell activity. We demonstrate that the Ras-PI3K-induced reduction in H3K56ac is associated with the proliferation and migration of tumor cells by targeting the transcription of tumor-associated genes. The depletion of the histone deacetyltransferases Sirt1 and Sirt2 rescues the Ras-PI3K-induced decrease in H3K56ac, gene transcription, tumor cell proliferation, and tumor cell migration. Furthermore, we demonstrate that the Ras-PI3K-AKT pathway regulates H3K56ac via the MDM2-dependent degradation of CREB-binding protein/p300. Taken together, the results of this study demonstrate that the Ras-PI3K signaling pathway targets specific epigenetic modifications in tumor cells.
authors.affiliation: Institute of Epigenetics and Cancer Research, School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Da-Liang
authors.initials: DL
authors.lastname: Wang
authors.forename: Su
authors.initials: S
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Fang-Lin
authors.initials: FL
authors.lastname: Sun
mesh_terms: D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006657:Histones / Q000737:chemistry*; D006801:Humans; D008239:Lysine / Q000737:chemistry*; D009369:Neoplasms / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D006657:Histones; D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins; D008239:Lysine