Hepatocyte-specific HDAC3 ablation promotes hepatocellular carcinoma in females by suppressing Foxa1/2
Abstract Background Hepatocellular carcinoma (HCC), the most common primary liver cancer, prevails mainly in males and has long been attributed to androgens and higher circumstantial levels of interleukin-6 (IL-6) produced by resident hepatic macrophages. Methods Constitutively hepatocyte-specific h...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-09-01
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| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12885-023-11393-1 |
| _version_ | 1827633981718265856 |
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| author | Yahong Xu Yongjie Zhu Zhenru Wu Shengfu Li Mingyang Shao Qing Tao Qing Xu Yuwei Chen Yuke Shu Menglin Chen Yongjie Zhou Yujun Shi |
| author_facet | Yahong Xu Yongjie Zhu Zhenru Wu Shengfu Li Mingyang Shao Qing Tao Qing Xu Yuwei Chen Yuke Shu Menglin Chen Yongjie Zhou Yujun Shi |
| author_sort | Yahong Xu |
| collection | DOAJ |
| description | Abstract Background Hepatocellular carcinoma (HCC), the most common primary liver cancer, prevails mainly in males and has long been attributed to androgens and higher circumstantial levels of interleukin-6 (IL-6) produced by resident hepatic macrophages. Methods Constitutively hepatocyte-specific histone deacetylase 3 (HDAC3)-deficient (HDAC3 LCKO ) mice and constitutively hepatocyte-specific HDAC3 knockout and systemic IL-6 simultaneously ablated (HDAC3 LCKO & IL-6 −/− ) mice were used in our study to explore the causes of sex differences in HCC. Additionally, we performed human HCC tissues with an IHC score. Correlation analysis and linear regression plots were constructed to reveal the association between HDAC3 and its candidate genes. To further elucidate that HDAC3 controls the expression of Foxa1/2, we knocked down HDAC3 in HUH7 liver cancer cells. Results We observed a contrary sex disparity, with an earlier onset and higher incidence of HCC in female mice when HDAC3 was selectively ablated in the liver. Loss of HDAC3 led to constant liver injury and the spontaneous development of HCC. Unlike the significant elevation of IL-6 in male mice at a very early age, female mice exhibit stable IL-6 levels, and IL-6 ablation did not eliminate the sex disparity in hepatocarcinogenesis in HDAC3-deficient mice. Oestrogen often protects the liver when combined with oestrogen receptor alpha (ERα); however, ovariectomy in HDAC3-ablated female mice significantly delayed tumourigenesis. The oestrogen-ERα axis can also play a role in tumour promotion in the absence of Foxa1 and Foxa2 in the receptor complex. Loss of HDAC3 profoundly reduced the expression of both Foxa1 and Foxa2 and impaired the binding between Foxa1/2 and ERα. Furthermore, a more frequent HDAC3 decrease accompanied by the simultaneous Foxa1/2 decline was found in female HCC compared to that in male HCC. Conclusion In summary, we reported that loss of HDAC3 reduces Foxa1/2 and thus promotes HCC development in females in an oestrogen-dependent manner. |
| first_indexed | 2024-03-09T15:06:53Z |
| format | Article |
| id | doaj.art-92582cae26084513a20fb1e61f504ad4 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-03-09T15:06:53Z |
| publishDate | 2023-09-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-92582cae26084513a20fb1e61f504ad42023-11-26T13:36:36ZengBMCBMC Cancer1471-24072023-09-0123111310.1186/s12885-023-11393-1Hepatocyte-specific HDAC3 ablation promotes hepatocellular carcinoma in females by suppressing Foxa1/2Yahong Xu0Yongjie Zhu1Zhenru Wu2Shengfu Li3Mingyang Shao4Qing Tao5Qing Xu6Yuwei Chen7Yuke Shu8Menglin Chen9Yongjie Zhou10Yujun Shi11Department of Pathology & Institute of Clinical Pathology, West China Hospital, Sichuan UniversityDepartment of Targeting Therapy & Immunology and Laboratory of Animal Tumor Models, Cancer Center, West China Hospital, Sichuan UniversityDepartment of Pathology & Institute of Clinical Pathology, West China Hospital, Sichuan UniversityDepartment of Pathology & Institute of Clinical Pathology, West China Hospital, Sichuan UniversityDepartment of Pathology & Institute of Clinical Pathology, West China Hospital, Sichuan UniversityDepartment of Pathology & Institute of Clinical Pathology, West China Hospital, Sichuan UniversityDepartment of Pathology & Institute of Clinical Pathology, West China Hospital, Sichuan UniversityDepartment of Pathology & Institute of Clinical Pathology, West China Hospital, Sichuan UniversityDepartment of Pathology & Institute of Clinical Pathology, West China Hospital, Sichuan UniversityDepartment of Pathology & Institute of Clinical Pathology, West China Hospital, Sichuan UniversityLaboratory of Liver Transplantation, West China Hospital, Sichuan UniversityDepartment of Pathology & Institute of Clinical Pathology, West China Hospital, Sichuan UniversityAbstract Background Hepatocellular carcinoma (HCC), the most common primary liver cancer, prevails mainly in males and has long been attributed to androgens and higher circumstantial levels of interleukin-6 (IL-6) produced by resident hepatic macrophages. Methods Constitutively hepatocyte-specific histone deacetylase 3 (HDAC3)-deficient (HDAC3 LCKO ) mice and constitutively hepatocyte-specific HDAC3 knockout and systemic IL-6 simultaneously ablated (HDAC3 LCKO & IL-6 −/− ) mice were used in our study to explore the causes of sex differences in HCC. Additionally, we performed human HCC tissues with an IHC score. Correlation analysis and linear regression plots were constructed to reveal the association between HDAC3 and its candidate genes. To further elucidate that HDAC3 controls the expression of Foxa1/2, we knocked down HDAC3 in HUH7 liver cancer cells. Results We observed a contrary sex disparity, with an earlier onset and higher incidence of HCC in female mice when HDAC3 was selectively ablated in the liver. Loss of HDAC3 led to constant liver injury and the spontaneous development of HCC. Unlike the significant elevation of IL-6 in male mice at a very early age, female mice exhibit stable IL-6 levels, and IL-6 ablation did not eliminate the sex disparity in hepatocarcinogenesis in HDAC3-deficient mice. Oestrogen often protects the liver when combined with oestrogen receptor alpha (ERα); however, ovariectomy in HDAC3-ablated female mice significantly delayed tumourigenesis. The oestrogen-ERα axis can also play a role in tumour promotion in the absence of Foxa1 and Foxa2 in the receptor complex. Loss of HDAC3 profoundly reduced the expression of both Foxa1 and Foxa2 and impaired the binding between Foxa1/2 and ERα. Furthermore, a more frequent HDAC3 decrease accompanied by the simultaneous Foxa1/2 decline was found in female HCC compared to that in male HCC. Conclusion In summary, we reported that loss of HDAC3 reduces Foxa1/2 and thus promotes HCC development in females in an oestrogen-dependent manner.https://doi.org/10.1186/s12885-023-11393-1HDAC3HCCSex differenceIL-6Foxa1Foxa2 |
| spellingShingle | Yahong Xu Yongjie Zhu Zhenru Wu Shengfu Li Mingyang Shao Qing Tao Qing Xu Yuwei Chen Yuke Shu Menglin Chen Yongjie Zhou Yujun Shi Hepatocyte-specific HDAC3 ablation promotes hepatocellular carcinoma in females by suppressing Foxa1/2 BMC Cancer HDAC3 HCC Sex difference IL-6 Foxa1 Foxa2 |
| title | Hepatocyte-specific HDAC3 ablation promotes hepatocellular carcinoma in females by suppressing Foxa1/2 |
| title_full | Hepatocyte-specific HDAC3 ablation promotes hepatocellular carcinoma in females by suppressing Foxa1/2 |
| title_fullStr | Hepatocyte-specific HDAC3 ablation promotes hepatocellular carcinoma in females by suppressing Foxa1/2 |
| title_full_unstemmed | Hepatocyte-specific HDAC3 ablation promotes hepatocellular carcinoma in females by suppressing Foxa1/2 |
| title_short | Hepatocyte-specific HDAC3 ablation promotes hepatocellular carcinoma in females by suppressing Foxa1/2 |
| title_sort | hepatocyte specific hdac3 ablation promotes hepatocellular carcinoma in females by suppressing foxa1 2 |
| topic | HDAC3 HCC Sex difference IL-6 Foxa1 Foxa2 |
| url | https://doi.org/10.1186/s12885-023-11393-1 |
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