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

Abstract

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.

Epigenetic regulation and therapeutic targets in the tumor microenvironment

“…In lung cancer, CCL2 expression was attenuated by EZH2-mediated H3K27me3 in the enhancer regions and DNMT1-mediated DNA methylation in the promoter regions [ 178 ], impeding M2-like phenotype of macrophages thereby facilitating metastasis and infiltration [ 179 ]. The same impact of CCL2/CCR2 axis on TAM further on tumor migration and invasion has also been demonstrated in breast cancer [ 180 ], constructing as a potential antitumor therapeutic target.…”

MNMST: topology of cell networks leverages identification of spatial domains from spatial transcriptomics data

“…4 I, where CXCL14 is upregulated in IDC, and COX6C is depressed in IDC. Furthermore, APOE , APOC1 , C1QA , C1QB , and NUPR1 are indicative markers of variations in the infiltration of tumor-associated macrophages (TAM) [ 38 , 39 ], where TAM infiltration is known to be associated with unfavorable survival outcomes in solid tumors. This association is owing to its role in promoting tumor angiogenesis, which induces tumor migration, invasion, and metastasis [ 40 – 42 ].…”

Antitumor therapy for breast cancer: Focus on tumor‐associated macrophages and nanosized drug delivery systems

“…Evidence shows that tumor cells educate macrophages toward the M2 activation status through secreting cytokines and lactic acid, which is conducive to their proliferation, invasion, and migration. Cytokines involved in macrophage recruitment, including CCL2, CCL5, CXCL12, and CSF1, have also been confirmed to promote M2 polarization of TAMs 74,91–93 . In addition to that, tumor cell‐derived TGFβ can promote M2 polarization by suppressing transcription factor EB (TFEB) activation and expression in macrophages 94 .…”

“…Cytokines involved in macrophage recruitment, including CCL2, CCL5, CXCL12, and CSF1, have also been confirmed to promote M2 polarization of TAMs. 74 , 91 , 92 , 93 In addition to that, tumor cell‐derived TGFβ can promote M2 polarization by suppressing transcription factor EB (TFEB) activation and expression in macrophages. 94 Polarized macrophages by TGF‐βplayed a role in promoting tumor growth.…”