YY1 complex in M2 macrophage promotes prostate cancer progression by upregulating IL-6
Background Tumor-associated macrophages are mainly polarized into the M2 phenotype, remodeling the tumor microenvironment and promoting tumor progression by secreting various cytokines.Methods Tissue microarray consisting of prostate cancer (PCa), normal prostate, and lymph node metastatic samples f...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2023-04-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/4/e006020.full |
| _version_ | 1797840045735936000 |
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| author | Lihua Zhang Ming Chen Shenghong Ju Kai Lu Bin Xu Wenchao Li Saisai Chen Jianping Wu Yue Hou Zonghao You Chuanjun Shu Xiaoying Wei Tiange Wu Naipeng Shi Guangyuan Zhang Shuqiu Chen Dingxiao Zhang |
| author_facet | Lihua Zhang Ming Chen Shenghong Ju Kai Lu Bin Xu Wenchao Li Saisai Chen Jianping Wu Yue Hou Zonghao You Chuanjun Shu Xiaoying Wei Tiange Wu Naipeng Shi Guangyuan Zhang Shuqiu Chen Dingxiao Zhang |
| author_sort | Lihua Zhang |
| collection | DOAJ |
| description | Background Tumor-associated macrophages are mainly polarized into the M2 phenotype, remodeling the tumor microenvironment and promoting tumor progression by secreting various cytokines.Methods Tissue microarray consisting of prostate cancer (PCa), normal prostate, and lymph node metastatic samples from patients with PCa were stained with Yin Yang 1 (YY1) and CD163. Transgenic mice overexpressing YY1 were constructed to observe PCa tumorigenesis. Furthermore, in vivo and in vitro experiments, including CRISPR-Cas9 knock-out, RNA sequencing, chromatin immunoprecipitation (ChIP) sequencing, and liquid–liquid phase separation (LLPS) assays, were performed to investigate the role and mechanism of YY1 in M2 macrophages and PCa tumor microenvironment.Results YY1 was highly expressed in M2 macrophages in PCa and was associated with poorer clinical outcomes. The proportion of tumor-infiltrated M2 macrophages increased in transgenic mice overexpressing YY1. In contrast, the proliferation and activity of anti-tumoral T lymphocytes were suppressed. Treatment targeting YY1 on M2 macrophages using an M2-targeting peptide-modified liposome carrier suppressed PCa cell lung metastasis and generated synergistic anti-tumoral effects with PD-1 blockade. IL-4/STAT6 pathway regulated YY1, and YY1 increased the macrophage-induced PCa progression by upregulating IL-6. Furthermore, by conducting H3K27ac-ChIP-seq in M2 macrophages and THP-1, we found that thousands of enhancers were gained during M2 macrophage polarization, and these M2-specific enhancers were enriched in YY1 ChIP-seq signals. In addition, an M2-specific IL-6 enhancer upregulated IL-6 expression through long-range chromatin interaction with IL-6 promoter in M2 macrophages. During M2 macrophage polarization, YY1 formed an LLPS, in which p300, p65, and CEBPB acted as transcriptional cofactors.Conclusions Phase separation of the YY1 complex in M2 macrophages upregulated IL-6 by promoting IL-6 enhancer–promoter interactions, thereby increasing PCa progression. |
| first_indexed | 2024-04-09T16:08:06Z |
| format | Article |
| id | doaj.art-ec9d96f2a8754401ade1e453d7bf41d6 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-09T16:08:06Z |
| publishDate | 2023-04-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-ec9d96f2a8754401ade1e453d7bf41d62023-04-25T03:30:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-04-0111410.1136/jitc-2022-006020YY1 complex in M2 macrophage promotes prostate cancer progression by upregulating IL-6Lihua Zhang0Ming Chen1Shenghong Ju2Kai Lu3Bin Xu4Wenchao Li5Saisai Chen6Jianping Wu7Yue Hou8Zonghao You9Chuanjun Shu10Xiaoying Wei11Tiange Wu12Naipeng Shi13Guangyuan Zhang14Shuqiu Chen15Dingxiao Zhang16National Clinical Research Center for Cardiovascular Diseases, NHC Key Laboratory of Clinical Research for Cardiovascular Medications, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Fuwai Hospital, Xicheng District, Beijing, ChinaDepartment of Regional Health Research, University of Southern Denmark Faculty of Health Sciences, Odense, DenmarkDepartment of Radiology, Southeast University Zhongda Hospital, Nanjing, China5 Office of Student Affairs, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Jiangsu Changzhou, ChinaSchool of Economics and Management, Tongji University, Shanghai, ChinaFrom the *Sheikh Zayed Center for Pediatric Surgical Innovation, Children’s National Health System; and †Division of Pediatric Otolaryngology, Children’s National Health System, Washington, DC.4Neuromodulation Global Research, Medtronic, Minneapolis, Minnesota, USAKey Laboratory of Biomedical Information Engineering of Ministry of Education, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi`an Jiaotong University, Xi`an, ChinaDepartment of Urology, Southeast University Zhongda Hospital, Nanjing, Jiangsu, ChinaDepartment of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, Jiangsu, ChinaDepartment of Pathology, Southeast University Zhongda Hospital, Nanjing, ChinaDepartment of Urology, Southeast University Zhongda Hospital, Nanjing, Jiangsu, ChinaDepartment of Urology, Southeast University Zhongda Hospital, Nanjing, Jiangsu, ChinaDepartment of Urology, Southeast University Zhongda Hospital, Nanjing, Jiangsu, ChinaDepartment of Urology, Southeast University Zhongda Hospital, Nanjing, Jiangsu, ChinaSchool of Biomedical Sciences, Hunan University, Changsha, Hunan, ChinaBackground Tumor-associated macrophages are mainly polarized into the M2 phenotype, remodeling the tumor microenvironment and promoting tumor progression by secreting various cytokines.Methods Tissue microarray consisting of prostate cancer (PCa), normal prostate, and lymph node metastatic samples from patients with PCa were stained with Yin Yang 1 (YY1) and CD163. Transgenic mice overexpressing YY1 were constructed to observe PCa tumorigenesis. Furthermore, in vivo and in vitro experiments, including CRISPR-Cas9 knock-out, RNA sequencing, chromatin immunoprecipitation (ChIP) sequencing, and liquid–liquid phase separation (LLPS) assays, were performed to investigate the role and mechanism of YY1 in M2 macrophages and PCa tumor microenvironment.Results YY1 was highly expressed in M2 macrophages in PCa and was associated with poorer clinical outcomes. The proportion of tumor-infiltrated M2 macrophages increased in transgenic mice overexpressing YY1. In contrast, the proliferation and activity of anti-tumoral T lymphocytes were suppressed. Treatment targeting YY1 on M2 macrophages using an M2-targeting peptide-modified liposome carrier suppressed PCa cell lung metastasis and generated synergistic anti-tumoral effects with PD-1 blockade. IL-4/STAT6 pathway regulated YY1, and YY1 increased the macrophage-induced PCa progression by upregulating IL-6. Furthermore, by conducting H3K27ac-ChIP-seq in M2 macrophages and THP-1, we found that thousands of enhancers were gained during M2 macrophage polarization, and these M2-specific enhancers were enriched in YY1 ChIP-seq signals. In addition, an M2-specific IL-6 enhancer upregulated IL-6 expression through long-range chromatin interaction with IL-6 promoter in M2 macrophages. During M2 macrophage polarization, YY1 formed an LLPS, in which p300, p65, and CEBPB acted as transcriptional cofactors.Conclusions Phase separation of the YY1 complex in M2 macrophages upregulated IL-6 by promoting IL-6 enhancer–promoter interactions, thereby increasing PCa progression.https://jitc.bmj.com/content/11/4/e006020.full |
| spellingShingle | Lihua Zhang Ming Chen Shenghong Ju Kai Lu Bin Xu Wenchao Li Saisai Chen Jianping Wu Yue Hou Zonghao You Chuanjun Shu Xiaoying Wei Tiange Wu Naipeng Shi Guangyuan Zhang Shuqiu Chen Dingxiao Zhang YY1 complex in M2 macrophage promotes prostate cancer progression by upregulating IL-6 Journal for ImmunoTherapy of Cancer |
| title | YY1 complex in M2 macrophage promotes prostate cancer progression by upregulating IL-6 |
| title_full | YY1 complex in M2 macrophage promotes prostate cancer progression by upregulating IL-6 |
| title_fullStr | YY1 complex in M2 macrophage promotes prostate cancer progression by upregulating IL-6 |
| title_full_unstemmed | YY1 complex in M2 macrophage promotes prostate cancer progression by upregulating IL-6 |
| title_short | YY1 complex in M2 macrophage promotes prostate cancer progression by upregulating IL-6 |
| title_sort | yy1 complex in m2 macrophage promotes prostate cancer progression by upregulating il 6 |
| url | https://jitc.bmj.com/content/11/4/e006020.full |
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