Regulation of CCL2 by EZH2 affects tumor-associated macrophages polarization and infiltration in breast cancer

doi:10.1038/s41419-022-05169-x

	Regulation of CCL2 by EZH2 affects tumor-associated macrophages polarization and infiltration in breast cancer
	Wang, Ya-fang1,2 ; Yu, Lei 1,3; Hu, Zong-long 1; Fang, Yan-fen 1; Shen, Yan-yan 1; Song, Min-fang4 ; Chen, Yi 1,3
	2022-08-29
发表期刊	CELL DEATH & DISEASE (IF:8.1[JCR-2023],8.6[5-Year])
ISSN	2041-4889
卷号	13 期号:8
发表状态	已发表
DOI	10.1038/s41419-022-05169-x
摘要	Tumor associated macrophages (TAMs) play an important role in tumorigenesis, development and anti-cancer drug therapy. However, very few epigenetic compounds have been elucidated to affect tumor growth by educating TAMs in the tumor microenvironment (TME). Herein, we identified that EZH2 performs a crucial role in the regulation of TAMs infiltration and protumoral polarization by interacting with human breast cancer (BC) cells. We showed that EZH2 inhibitors-treated BC cells induced M2 macrophage polarization in vitro and in vivo, while EZH2 knockdown exhibited the opposite effect. Mechanistically, inhibition of EZH2 histone methyltransferase alone by EZH2 inhibitors in breast cancer cells could reduce the enrichment of H3K27me3 on CCL2 gene promoter, elevate CCL2 transcription and secretion, contributing to the induction of M2 macrophage polarization and recruitment in TME, which reveal a potential explanation behind the frustrating results of EZH2 inhibitors against breast cancer. On the contrary, EZH2 depletion led to DNA demethylation and subsequent upregulation of miR-124-3p level, which inhibited its target CCL2 expression in the tumor cells, causing arrest of TAMs M2 polarization. Taken together, these data suggested that EZH2 can exert opposite regulatory effects on TAMs polarization through its enzymatic or non-enzymatic activities. Our results also imply that the effect of antitumor drugs on TAMs may affect its therapeutic efficacy, and the combined application with TAMs modifiers should be warranted to achieve great clinical success.
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收录类别	SCI ; SCIE
语种	英语
资助项目	National Natural Sciences foundation of China[81803557] ; Lingang Laboratory[LG202103-02-05]
WOS研究方向	Cell Biology
WOS类目	Cell Biology
WOS记录号	WOS:000847374000002
出版者	SPRINGERNATURE
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/229832
专题	生命科学与技术学院_博士生免疫化学研究所_特聘教授组_蒋华良组
通讯作者	Wang, Ya-fang; Chen, Yi
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai, Peoples R China 2.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai, Peoples R China 3.Univ Chinese Acad Sci, Beijing, Peoples R China 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
第一作者单位	免疫化学研究所
通讯作者单位	免疫化学研究所
推荐引用方式 GB/T 7714	Wang, Ya-fang,Yu, Lei,Hu, Zong-long,et al. Regulation of CCL2 by EZH2 affects tumor-associated macrophages polarization and infiltration in breast cancer[J]. CELL DEATH & DISEASE,2022,13(8).
APA	Wang, Ya-fang.,Yu, Lei.,Hu, Zong-long.,Fang, Yan-fen.,Shen, Yan-yan.,...&Chen, Yi.(2022).Regulation of CCL2 by EZH2 affects tumor-associated macrophages polarization and infiltration in breast cancer.CELL DEATH & DISEASE,13(8).
MLA	Wang, Ya-fang,et al."Regulation of CCL2 by EZH2 affects tumor-associated macrophages polarization and infiltration in breast cancer".CELL DEATH & DISEASE 13.8(2022).