title: HDAC inhibition impedes epithelial-mesenchymal plasticity and suppresses metastatic, castration-resistant prostate cancer.
abstract: PI3K (phosphoinositide 3-kinase)/AKT and RAS/MAPK (mitogen-activated protein kinase) pathway coactivation in the prostate epithelium promotes both epithelial-mesenchymal transition (EMT) and metastatic castration-resistant prostate cancer (mCRPC), which is currently incurable. To study the dynamic regulation of the EMT process, we developed novel genetically defined cellular and in vivo model systems from which epithelial, EMT and mesenchymal-like tumor cells with Pten deletion and Kras activation can be isolated. When cultured individually, each population has the capacity to regenerate all three tumor cell populations, indicative of epithelial-mesenchymal plasticity. Despite harboring the same genetic alterations, mesenchymal-like tumor cells are resistant to PI3K and MAPK pathway inhibitors, suggesting that epigenetic mechanisms may regulate the EMT process, as well as dictate the heterogeneous responses of cancer cells to therapy. Among differentially expressed epigenetic regulators, the chromatin remodeling protein HMGA2 is significantly upregulated in EMT and mesenchymal-like tumors cells, as well as in human mCRPC. Knockdown of HMGA2, or suppressing HMGA2 expression with the histone deacetylase inhibitor LBH589, inhibits epithelial-mesenchymal plasticity and stemness activities in vitro and markedly reduces tumor growth and metastasis in vivo through successful targeting of EMT and mesenchymal-like tumor cells. Importantly, LBH589 treatment in combination with castration prevents mCRPC development and significantly prolongs survival following castration by enhancing p53 and androgen receptor acetylation and in turn sensitizing castration-resistant mesenchymal-like tumor cells to androgen deprivation therapy. Taken together, these findings demonstrate that cellular plasticity is regulated epigenetically, and that mesenchymal-like tumor cell populations in mCRPC that are resistant to conventional and targeted therapies can be effectively treated with the epigenetic inhibitor LBH589.
authors.affiliation: Molecular Biology Institute, UCLA, Los Angeles, CA, USA.|Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ruscetti
authors.affiliation: Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA.
authors.forename: E L
authors.initials: EL
authors.lastname: Dadashian
authors.affiliation: School of Life Sciences, Peking University, Beijing, China.
authors.forename: W
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Quach
authors.affiliation: Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Mulholland
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Tran
authors.affiliation: Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Kobayashi
authors.affiliation: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Bianchi-Frias
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: Molecular Biology Institute, UCLA, Los Angeles, CA, USA.|Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA.|School of Life Sciences, Peking University, Beijing, China.
authors.forename: H
authors.initials: H
authors.lastname: Wu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D000077767:Panobinostat; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D020928:Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; D000077767:Panobinostat; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); C487757:Pten protein, mouse; C495971:Hras protein, mouse