Novel AKT1-GLI3-VMP1 Pathway Mediates KRAS Oncogene-induced Autophagy in Cancer Cells

• Published in: The Journal of biological chemistry Vol. 287; no. 30; pp. 25325 - 25334
• Main Authors: Lo Ré, Andrea E., Fernández-Barrena, Maite G., Almada, Luciana L., Mills, Lisa D., Elsawa, Sherine F., Lund, George, Ropolo, Alejandro, Molejon, Maria I., Vaccaro, Maria I., Fernandez-Zapico, Martin E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.07.2012; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Autophagy; Bioenergetics; CHO Cells; Cricetinae; Cricetulus; Gene Expression; Gene Expression Regulation, Neoplastic - genetics; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; HeLa Cells; Humans; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Mice; Neoplasms - genetics; Neoplasms - mortality; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Oncogene; p300-CBP Transcription Factors - genetics; p300-CBP Transcription Factors - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; ras Proteins - genetics; ras Proteins - metabolism; Response Elements - genetics; Signal Transduction; Signaling; Zinc Finger Protein Gli3; Signaling; Gene Expression; Bioenergetics; Autophagy; Oncogene
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.370809

Background: Autophagy plays a role in cancer development. Results: Oncogenic KRAS induces Vacuole Membrane Protein 1 (VMP1) through a novel AKT1-GLI3-p300 pathway and requires VMP1 to regulate autophagy in cancer cells. Conclusion: Define a novel pathway initiated by the oncogene KRAS regulating autophagy. Significance: These findings contribute to the understanding of the mechanism underlying oncogene-induced autophagy. 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.