title: Differential effects of RUNX2 on the androgen receptor in prostate cancer: synergistic stimulation of a gene set exemplified by SNAI2 and subsequent invasiveness.
abstract: Changes to androgen signaling during prostate carcinogenesis are associated with both inhibition of cellular differentiation and promotion of malignant phenotypes. The androgen receptor (AR)-binding transcription factor RUNX2 has been linked to prostate cancer progression but the underlying mechanisms have not been fully defined. In this study, we investigated the genome-wide influence of RUNX2 on androgen-induced gene expression and AR DNA binding in prostate cancer cells. RUNX2 inhibited the androgen response partly by promoting the dissociation of AR from its target genes such as the tumor suppressor NKX3-1. However, AR activity persists in the presence of RUNX2 at other AR target genes, some of which are cooperatively stimulated by androgen and RUNX2 signaling. These genes are associated with putative enhancers co-occupied by AR and RUNX2. One such gene, the invasion-promoting Snail family transcription factor SNAI2, was co-activated by AR and RUNX2. Indeed, these two transcription factors together, but neither alone stimulated prostate cancer cell invasiveness, which could be abolished by SNAI2 silencing. Furthermore, an immunohistochemical analysis of SNAI2 in archived primary prostate cancer specimens revealed a correlation with the RUNX2 histoscore, and simultaneous strong staining for SNAI2, RUNX2, and AR (but not any pair alone) was associated with disease recurrence. Overall, our findings suggest cooperation between AR and RUNX in the stimulation of oncogenes such as SNAI2, which might be targeted for individualized prostate cancer therapy.
authors.affiliation: Authors' Affiliations: Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine; Institute for Genetic Medicine; USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles; Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CaliforniaAuthors' Affiliations: Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine; Institute for Genetic Medicine; USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles; Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California glittle@usc.edu frenkel@usc.edu.
authors.forename: Gillian H
authors.initials: GH
authors.lastname: Little
authors.affiliation: Authors' Affiliations: Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine; Institute for Genetic Medicine; USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles; Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CaliforniaAuthors' Affiliations: Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine; Institute for Genetic Medicine; USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles; Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California.
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Baniwal
authors.affiliation: Authors' Affiliations: Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine; Institute for Genetic Medicine; USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles; Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CaliforniaAuthors' Affiliations: Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine; Institute for Genetic Medicine; USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles; Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California.
authors.forename: Helty
authors.initials: H
authors.lastname: Adisetiyo
authors.affiliation: Authors' Affiliations: Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine; Institute for Genetic Medicine; USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles; Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CaliforniaAuthors' Affiliations: Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine; Institute for Genetic Medicine; USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles; Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California.
authors.forename: Susan
authors.initials: S
authors.lastname: Groshen
authors.affiliation: Authors' Affiliations: Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine; Institute for Genetic Medicine; USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles; Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CaliforniaAuthors' Affiliations: Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine; Institute for Genetic Medicine; USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles; Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California.
authors.forename: Nyam-Osor
authors.initials: NO
authors.lastname: Chimge
authors.affiliation: Authors' Affiliations: Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine; Institute for Genetic Medicine; USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles; Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Authors' Affiliations: Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine; Institute for Genetic Medicine; USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles; Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California.
authors.forename: Omar
authors.initials: O
authors.lastname: Khalid
authors.affiliation: Authors' Affiliations: Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine; Institute for Genetic Medicine; USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles; Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California.
authors.forename: Debra
authors.initials: D
authors.lastname: Hawes
authors.affiliation: Authors' Affiliations: Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine; Institute for Genetic Medicine; USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles; Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California.
authors.forename: Jeremy O
authors.initials: JO
authors.lastname: Jones
authors.affiliation: Authors' Affiliations: Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine; Institute for Genetic Medicine; USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles; Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CaliforniaAuthors' Affiliations: Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine; Institute for Genetic Medicine; USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles; Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California.
authors.forename: Jacek
authors.initials: J
authors.lastname: Pinski
authors.affiliation: Authors' Affiliations: Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine; Institute for Genetic Medicine; USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles; Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California.
authors.forename: Dustin E
authors.initials: DE
authors.lastname: Schones
authors.affiliation: Authors' Affiliations: Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine; Institute for Genetic Medicine; USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles; Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CaliforniaAuthors' Affiliations: Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine; Institute for Genetic Medicine; USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles; Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CaliforniaAuthors' Affiliations: Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine; Institute for Genetic Medicine; USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles; Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California glittle@usc.edu frenkel@usc.edu.
authors.forename: Baruch
authors.initials: B
authors.lastname: Frenkel
mesh_terms: D000818:Animals; D001706:Biopsy; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000494:pharmacology; D004318:Doxycycline / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human; D011944:Receptors, Androgen; C000604408:SNAI2 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D013196:Dihydrotestosterone; D004318:Doxycycline