Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells

Andrea E. Lo Ré, Maite G. Fernández-Barrena, Luciana L. Almada, Lisa D. Mills, Sherine F. Elsawa, George Lund, Alejandro Ropolo, Maria I. Molejon, Maria I. Vaccaro, Martin E. Fernandez-Zapico

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40 Scopus citations

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 ofVMP1upstream 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.

Original languageEnglish (US)
Pages (from-to)25325-25334
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number30
DOIs
StatePublished - Jul 20 2012

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Lo Ré, A. E., Fernández-Barrena, M. G., Almada, L. L., Mills, L. D., Elsawa, S. F., Lund, G., Ropolo, A., Molejon, M. I., Vaccaro, M. I., & Fernandez-Zapico, M. E. (2012). Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells. Journal of Biological Chemistry, 287(30), 25325-25334. https://doi.org/10.1074/jbc.M112.370809