title: GATA2 facilitates steroid receptor coactivator recruitment to the androgen receptor complex.
abstract: The androgen receptor (AR) is a key driver of prostate cancer (PC), even in the state of castration-resistant PC (CRPC) and frequently even after treatment with second-line hormonal therapies such as abiraterone and enzalutamide. The persistence of AR activity via both ligand-dependent and ligand-independent mechanisms (including constitutively active AR splice variants) highlights the unmet need for alternative approaches to block AR signaling in CRPC. We investigated the transcription factor GATA-binding protein 2 (GATA2) as a regulator of AR signaling and an actionable therapeutic target in PC. We demonstrate that GATA2 directly promotes expression of both full-length and splice-variant AR, resulting in a strong positive correlation between GATA2 and AR expression in both PC cell lines and patient specimens. Conversely, GATA2 expression is repressed by androgen and AR, suggesting a negative feedback regulatory loop that, upon androgen deprivation, derepresses GATA2 to contribute to AR overexpression in CRPC. Simultaneously, GATA2 is necessary for optimal transcriptional activity of both full-length and splice-variant AR. GATA2 colocalizes with AR and Forkhead box protein A1 on chromatin to enhance recruitment of steroid receptor coactivators and formation of the transcriptional holocomplex. In agreement with these important functions, high GATA2 expression and transcriptional activity predicted worse clinical outcome in PC patients. A GATA2 small molecule inhibitor suppressed the expression and transcriptional function of both full-length and splice-variant AR and exerted potent anticancer activity against PC cell lines. We propose pharmacological inhibition of GATA2 as a first-in-field approach to target AR expression and function and improve outcomes in CRPC.
authors.affiliation: Departments of Medicine, Molecular and Cellular Biology.
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.affiliation: Molecular and Cellular Biology.
authors.forename: Rainer B
authors.initials: RB
authors.lastname: Lanz
authors.affiliation: Departments of Medicine, Molecular and Cellular Biology.
authors.forename: Warren
authors.initials: W
authors.lastname: Fiskus
authors.affiliation: Departments of Medicine.
authors.forename: Chuandong
authors.initials: C
authors.lastname: Geng
authors.affiliation: Molecular and Cellular Biology.
authors.forename: Ping
authors.initials: P
authors.lastname: Yi
authors.affiliation: Molecular and Cellular Biology.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Hartig
authors.affiliation: Molecular and Cellular Biology.
authors.forename: Kimal
authors.initials: K
authors.lastname: Rajapakshe
authors.affiliation: Departments of Medicine.
authors.forename: John
authors.initials: J
authors.lastname: Shou
authors.affiliation: Pharmacology, and.
authors.forename: Liping
authors.initials: L
authors.lastname: Wei
authors.affiliation: Departments of Medicine.
authors.forename: Shrijal S
authors.initials: SS
authors.lastname: Shah
authors.affiliation: Departments of Medicine, Molecular and Cellular Biology.
authors.forename: Christopher
authors.initials: C
authors.lastname: Foley
authors.affiliation: Departments of Medicine.
authors.forename: Sue Anne
authors.initials: SA
authors.lastname: Chew
authors.affiliation: Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, 70130;
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Eedunuri
authors.affiliation: Departments of Medicine.
authors.forename: Diego J
authors.initials: DJ
authors.lastname: Bedoya
authors.affiliation: Molecular and Cellular Biology.
authors.forename: Qin
authors.initials: Q
authors.lastname: Feng
authors.affiliation: Laboratory for Systems Biology and Medicine, The Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan 153-8904; and.
authors.forename: Takashi
authors.initials: T
authors.lastname: Minami
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
authors.affiliation: Dan L. Duncan Cancer Center-Biostatistics, and.
authors.forename: Anna
authors.initials: A
authors.lastname: Frolov
authors.affiliation: Molecular and Cellular Biology.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Weigel
authors.affiliation: Dan L. Duncan Cancer Center-Biostatistics, and.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.affiliation: Pathology and Immunology, Michael E. DeBakey Veterans Affairs Medical Center, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Rosen
authors.affiliation: Pharmacology, and.
authors.forename: Timothy
authors.initials: T
authors.lastname: Palzkill
authors.affiliation: Pathology and Immunology, Michael E. DeBakey Veterans Affairs Medical Center, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Michael M
authors.initials: MM
authors.lastname: Ittmann
authors.affiliation: Pharmacology, and.
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Song
authors.affiliation: Molecular and Cellular Biology, coarfa@bcm.edu berto@bcm.edu mitsiade@bcm.edu.
authors.forename: Cristian
authors.initials: C
authors.lastname: Coarfa
authors.affiliation: Molecular and Cellular Biology, coarfa@bcm.edu berto@bcm.edu mitsiade@bcm.edu.
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.affiliation: Departments of Medicine, Molecular and Cellular Biology, coarfa@bcm.edu berto@bcm.edu mitsiade@bcm.edu.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsiades
mesh_terms: D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D050989:GATA2 Transcription Factor / Q000502:physiology*; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D006801:Humans; D008297:Male; D056918:Nuclear Receptor Coactivators / Q000378:metabolism*; D011379:Prognosis; D011944:Receptors, Androgen / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D002843:Chromatin; C496499:FOXA1 protein, human; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D056918:Nuclear Receptor Coactivators; D011944:Receptors, Androgen
keywords: AR signaling; GATA2; prostate cancer; small molecule inhibitor; steroid receptor coactivator