Loss of HDAC-Mediated Repression and Gain of NF-κB Activation Underlie Cytokine Induction in ARID1A- and PIK3CA-Mutation-Driven Ovarian Cancer.
ARID1A is frequently mutated in ovarian clear cell carcinoma (OCCC) and often co-exists with activating mutations of PIK3CA. Although induction of pro-inflammatory cytokines has been observed in this cancer, the mechanism by which the two mutations synergistically activate cytokine genes remains elusive. Here, we established an in vitro model of OCCC by introducing ARID1A knockdown and mutant PIK3CA into a normal human ovarian epithelial cell line, resulting in cell transformation and cytokine gene induction. We demonstrate that loss of ARID1A impairs the recruitment of the Sin3A-HDAC complex, while the PIK3CA mutation releases RelA from IκB, leading to cytokine gene activation. We show that an NF-κB inhibitor partly attenuates the proliferation of OCCC and improves the efficacy of carboplatin both in cell culture and in a mouse model. Our study thus reveals the mechanistic link between ARID1A/PIK3CA mutations and cytokine gene induction in OCCC and suggests that NF-κB inhibition could be a potential therapeutic option.
Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Division of Hematology/Oncology, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA.
Minchul
M
Kim
Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Division of Hematology/Oncology, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA.
Falong
F
Lu
Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Division of Hematology/Oncology, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA. Electronic address: yzhang@genetics.med.harvard.edu.
Yi
Y
Zhang
D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016190:Carboplatin / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C112476:ARID1A protein, human; D000970:Antineoplastic Agents; D016207:Cytokines; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; C498143:RELA protein, human; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D051996:Transcription Factor RelA; D014157:Transcription Factors; D000072000:NF-KappaB Inhibitor alpha; D016190:Carboplatin; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex
ARID1A; HDAC; PIK3CA; RelA; ovarian clear cell carcinoma; pro-inflammatory cytokine
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