title: Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells.
abstract: Autophagy is an evolutionarily conserved degradation process of cytoplasmic cellular constituents. It has been suggested that autophagy plays a role in tumor promotion and progression downstream oncogenic pathways; however, the molecular mechanisms underlying this phenomenon have not been elucidated. Here, we provide both in vitro and in vivo evidence of a novel signaling pathway whereby the oncogene KRAS induces the expression of VMP1, a molecule needed for the formation of the authophagosome and capable of inducing autophagy, even under nutrient-replete conditions. RNAi experiments demonstrated that KRAS requires VMP1 to induce autophagy. Analysis of the mechanisms identified GLI3, a transcription factor regulated by the Hedgehog pathway, as an effector of KRAS signaling. GLI3 regulates autophagy as well as the expression and promoter activity of VMP1 in a Hedgehog-independent manner. Chromatin immunoprecipitation assays demonstrated that GLI3 binds to the VMP1 promoter and complexes with the histone acetyltransferase p300 to regulate promoter activity. Knockdown of p300 impaired KRAS- and GLI3-induced activation of this promoter. Finally, we identified the PI3K-AKT1 pathway as the signaling pathway mediating the expression and promoter activity of VMP1 upstream of the GLI3-p300 complex. Together, these data provide evidence of a new regulatory mechanism involved in autophagy that integrates this cellular process into the molecular network of events regulating oncogene-induced autophagy.
authors.affiliation: Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Lo Ré
authors.forename: Maite G
authors.initials: MG
authors.lastname: Fernández-Barrena
authors.forename: Luciana L
authors.initials: LL
authors.lastname: Almada
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Mills
authors.forename: Sherine F
authors.initials: SF
authors.lastname: Elsawa
authors.forename: George
authors.initials: G
authors.lastname: Lund
authors.forename: Alejandro
authors.initials: A
authors.lastname: Ropolo
authors.forename: Maria I
authors.initials: MI
authors.lastname: Molejon
authors.forename: Maria I
authors.initials: MI
authors.lastname: Vaccaro
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
mesh_terms: D000818:Animals; D001343:Autophagy; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006367:HeLa Cells; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000401:mortality*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction; D000074290:Zinc Finger Protein Gli3; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D000074290:Zinc Finger Protein Gli3; D050880:p300-CBP Transcription Factors; D018631:ras Proteins; D000099224:p300-CBP-Associated Factor; C065683:GLI3 protein, human; C465571:Gli3 protein, mouse; C117307:KRAS protein, human; C526584:VMP1 protein, human; C494918:AKT1 protein, human; C514862:Akt1 protein, mouse; C495971:Hras protein, mouse