title: HDAC4-regulated STAT1 activation mediates platinum resistance in ovarian cancer.
abstract: Ovarian cancer frequently acquires resistance to platinum chemotherapy, representing a major challenge for improving patient survival. Recent work suggests that resistant clones exist within a larger drug-sensitive cell population prior to chemotherapy, implying that resistance is selected for rather than generated by treatment. We sought to compare clinically derived, intrapatient paired models of initial platinum response and subsequent resistant relapse to define molecular determinants of evolved resistance. Transcriptional analysis of a matched cell line series from three patients with high-grade serous ovarian cancer before and after development of clinical platinum resistance (PEO1/PEO4/PEO6, PEA1/PEA2, PEO14/PEO23) identified 91 up- and 126 downregulated genes common to acquired resistance. Significantly enhanced apoptotic response to platinum treatment in resistant cells was observed following knockdown of histone deacetylase (HDAC) 4, FOLR2, PIK3R1, or STAT1 (P < 0.05). Interestingly, HDAC4 and STAT1 were found to physically interact. Acetyl-STAT1 was detected in platinum-sensitive cells but not in HDAC4 overexpressing platinum-resistant cells from the same patient. In resistant cells, STAT1 phosphorylation/nuclear translocation was seen following platinum exposure, whereas silencing of HDAC4 increased acetyl-STAT1 levels, prevented platinum-induced STAT1 activation, and restored cisplatin sensitivity. Conversely, matched sensitive cells were refractory to STAT1 phosphorylation on platinum treatment. Analysis of 16 paired tumor biopsies taken before and after development of clinical platinum resistance showed significantly increased HDAC4 expression in resistant tumors [n = 7 of 16 (44%); P = 0.04]. Therefore, clinical selection of HDAC4-overexpressing tumor cells upon exposure to chemotherapy promotes STAT1 deacetylation and cancer cell survival. Together, our findings identify HDAC4 as a novel, therapeutically tractable target to counter platinum resistance in ovarian cancer.
authors.affiliation: Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, Edinburgh, United Kingdom. e.stronach@imperial.ac.uk
authors.forename: Euan A
authors.initials: EA
authors.lastname: Stronach
authors.forename: Albandri
authors.initials: A
authors.lastname: Alfraidi
authors.forename: Nona
authors.initials: N
authors.lastname: Rama
authors.forename: Christoph
authors.initials: C
authors.lastname: Datler
authors.forename: James B
authors.initials: JB
authors.lastname: Studd
authors.forename: Roshan
authors.initials: R
authors.lastname: Agarwal
authors.forename: Tankut G
authors.initials: TG
authors.lastname: Guney
authors.forename: Charlie
authors.initials: C
authors.lastname: Gourley
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Hennessy
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Robert
authors.initials: R
authors.lastname: Brown
authors.forename: Roberto
authors.initials: R
authors.lastname: Dina
authors.forename: Hani
authors.initials: H
authors.lastname: Gabra
mesh_terms: D000107:Acetylation; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism*
chemical_list: D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C400300:HDAC4 protein, human; D006655:Histone Deacetylases; D002945:Cisplatin