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Vorinostat decrease M2 macrophage polarization through ARID1A6488delG/HDAC6/IL-10 signaling pathway in endometriosis-associated ovarian carcinoma.

  • Hsieh, Tsung-Hua1
  • Hsu, Chia-Yi2
  • Wu, Chia-Wei3
  • Wang, Shih-Ho4
  • Yeh, Cheng-Hsi4
  • Cheng, Kuang-Hung5
  • Tsai, Eing-Mei2
  • 1 Department of Medical Research, E-Da Hospital/E-Da Cancer Hospital, I-Shou University, Kaohsiung 82445, Taiwan. Electronic address: [email protected]. , (Taiwan)
  • 2 Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan. , (Taiwan)
  • 3 Department of Medical Research, E-Da Hospital/E-Da Cancer Hospital, I-Shou University, Kaohsiung 82445, Taiwan. , (Taiwan)
  • 4 Division of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. , (Taiwan)
  • 5 Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan. , (Taiwan)
Published Article
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Publication Date
May 01, 2023
DOI: 10.1016/j.biopha.2023.114500
PMID: 36958195


Endometriosis is a common disease in women and may be one of the factors that induces malignant epithelial ovarian tumors. Previous studies suggested that endometriosis is related to ARID1A mutation mediating the expression of HDAC6, but the detailed pathogenic mechanism is still unclear. First, we collected endometriosis-associated ovarian carcinoma (EAOC) clinical samples and examined the expression of HDAC6. Our results found that the high HDAC6 expression group was positively correlated with EAOC histology (P = 0.015), stage (P < 0.000), and tumor size (P < 0.000) and inversely correlated with survival (P < 0.000). We also found that ARID1A6488delG/HDAC6 induced M2 polarization of macrophages through IL-10. In addition, the HDAC inhibitor (HDACi) vorinostat inhibited cell growth and blocked the effect of HDAC6. Tomographic microscopy was used to monitor the live cell morphology of these treated cells, and we found that vorinostat treatment resulted in substantial cell apoptosis by 3 h 42 min. Next, we established a transgenic mouse model of EAOC and found that vorinostat significantly reduced the size of ovarian tumors by inhibiting M2 macrophage polarization in mice. Together, these data demonstrate that the signaling pathway of E4F1/ARID1A6488delG/HDAC6/GATA3 mediates macrophage polarization and provides a novel immune cell-associated therapeutic strategy targeting IL-10 in EAOC. Copyright © 2023. Published by Elsevier Masson SAS.

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