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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 sample...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10152059/ https://www.ncbi.nlm.nih.gov/pubmed/37094986 http://dx.doi.org/10.1136/jitc-2022-006020 |
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author | Chen, Saisai Lu, Kai Hou, Yue You, Zonghao Shu, Chuanjun Wei, Xiaoying Wu, Tiange Shi, Naipeng Zhang, Guangyuan Wu, Jianping Chen, Shuqiu Zhang, Lihua Li, Wenchao Zhang, Dingxiao Ju, Shenghong Chen, Ming Xu, Bin |
author_facet | Chen, Saisai Lu, Kai Hou, Yue You, Zonghao Shu, Chuanjun Wei, Xiaoying Wu, Tiange Shi, Naipeng Zhang, Guangyuan Wu, Jianping Chen, Shuqiu Zhang, Lihua Li, Wenchao Zhang, Dingxiao Ju, Shenghong Chen, Ming Xu, Bin |
author_sort | Chen, Saisai |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-10152059 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-101520592023-05-03 YY1 complex in M2 macrophage promotes prostate cancer progression by upregulating IL-6 Chen, Saisai Lu, Kai Hou, Yue You, Zonghao Shu, Chuanjun Wei, Xiaoying Wu, Tiange Shi, Naipeng Zhang, Guangyuan Wu, Jianping Chen, Shuqiu Zhang, Lihua Li, Wenchao Zhang, Dingxiao Ju, Shenghong Chen, Ming Xu, Bin J Immunother Cancer Basic Tumor Immunology 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. BMJ Publishing Group 2023-04-24 /pmc/articles/PMC10152059/ /pubmed/37094986 http://dx.doi.org/10.1136/jitc-2022-006020 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Basic Tumor Immunology Chen, Saisai Lu, Kai Hou, Yue You, Zonghao Shu, Chuanjun Wei, Xiaoying Wu, Tiange Shi, Naipeng Zhang, Guangyuan Wu, Jianping Chen, Shuqiu Zhang, Lihua Li, Wenchao Zhang, Dingxiao Ju, Shenghong Chen, Ming Xu, Bin YY1 complex in M2 macrophage promotes prostate cancer progression by upregulating IL-6 |
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 |
topic | Basic Tumor Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10152059/ https://www.ncbi.nlm.nih.gov/pubmed/37094986 http://dx.doi.org/10.1136/jitc-2022-006020 |
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