title: Gli Transcription Factors Mediate the Oncogenic Transformation of Prostate Basal Cells Induced by a Kras-Androgen Receptor Axis.
abstract: Although the differentiation of oncogenically transformed basal progenitor cells is one of the key steps in prostate tumorigenesis, the mechanisms mediating this cellular process are still largely unknown. Here we demonstrate that an expanded p63+and CK5+basal/progenitor cell population, induced by the concomitant activation of oncogenic Kras(G12D) and androgen receptor (AR) signaling, underwent cell differentiation in vivo The differentiation process led to suppression of p63-expressing cells with a decreased number of CK5+basal cells but an increase of CK8+luminal tumorigenic cells and revealed a hierarchal lineage pattern consisting of p63+/CK5+progenitor, CK5+/CK8+transitional progenitor, and CK8+differentiated luminal cells. Further analysis of the phenotype showed that Kras-AR axis-induced tumorigenesis was mediated by Gli transcription factors. Combined blocking of the activators of this family of proteins (Gli1 and Gli2) inhibited the proliferation of p63+and CK5+basal/progenitor cells and development of tumors. Finally, we identified that Gli1 and Gli2 exhibited different functions in the regulation of p63 expression or proliferation of p63+cells in Kras-AR driven tumors. Gli2, but not Gli1, transcriptionally regulated the expression levels of p63 and prostate sphere formation. Our study provides evidence of a novel mechanism mediating pathological dysregulation of basal/progenitor cells through the differential activation of the Gli transcription factors. Also, these findings define Gli proteins as new downstream mediators of the Kras-AR axis in prostate carcinogenesis and open a potential therapeutic avenue of targeting prostate cancer progression by inhibiting Gli signaling.
authors.affiliation: From the Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602.
authors.forename: Meng
authors.initials: M
authors.lastname: Wu
authors.affiliation: From the Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602.
authors.forename: Lishann
authors.initials: L
authors.lastname: Ingram
authors.affiliation: the Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Ezequiel J
authors.initials: EJ
authors.lastname: Tolosa
authors.affiliation: the Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Renzo E
authors.initials: RE
authors.lastname: Vera
authors.affiliation: From the Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602.
authors.forename: Qianjin
authors.initials: Q
authors.lastname: Li
authors.affiliation: From the Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602.
authors.forename: Sungjin
authors.initials: S
authors.lastname: Kim
authors.affiliation: From the Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Ma
authors.affiliation: the Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Demetri D
authors.initials: DD
authors.lastname: Spyropoulos
authors.affiliation: the Department of Chemistry and Physics, Florida Gulf Coast University, Fort Myers, Florida 33965, and.
authors.forename: Zanna
authors.initials: Z
authors.lastname: Beharry
authors.affiliation: the Department of Pathology, School of Medicine, Duke University, Durham, North Carolina 27710.
authors.forename: Jiaoti
authors.initials: J
authors.lastname: Huang
authors.affiliation: the Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
authors.affiliation: From the Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602, caihj@uga.edu.
authors.forename: Houjian
authors.initials: H
authors.lastname: Cai
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1 / Q000235:genetics / Q000378:metabolism*; D000075746:Zinc Finger Protein Gli2
chemical_list: C400551:GLI1 protein, human; C082593:GLI2 protein, human; C498520:Gli1 protein, mouse; C117307:KRAS protein, human; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011944:Receptors, Androgen; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C486419:Trp63 protein, mouse; D025521:Tumor Suppressor Proteins; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: GTPase Kras (KRAS); Hedgehog signaling pathway; androgen receptor; p63; prostate cancer