EZH2 enhances expression of CCL5 to promote recruitment of macrophages and invasion in lung cancer

Abstract

EZH2 (enhancer of zeste homolog 2) regulates epigenetic gene silencing and functions as critical regulators in various tumor progression. Macrophages infiltration promotes cancer development via stimulating tumor cell migration and invasion. However, the effect of EZH2 on macrophages infiltration, cell invasion, and migration of lung cancer remains to be investigated. In this study, we found that knockdown of EZH2 inhibited macrophages chemotaxis and decreased chemokine ligand 5 (CCL5). Wound-healing and transwell assays results showed that migration and invasion of lung cancer cells was inhibited by EZH2 deletion. Moreover, EZH2 overexpression increased CCL5 expression. Loss-of functional assay indicated that the promotion ability of EZH2 on macrophages chemotaxis was inhibited by CCL5 knockdown.Mechanistically, the promotion ability of EZH2 on cell migration and invasion of lung cancer was also inhibited by CCL5 knockdown. The in vivo subcutaneous xenotransplanted tumor model also revealed that silence of EZH2 suppressed lung cancer metastasis and macrophages infiltration via regulation of CCL5. In conclusion, our findings indicated that EZH2 promoted lung cancer metastasis and macrophages infiltration via upregulation of CCL5, which might be the underlying mechanism of EZH2-induced lung cancer cell progression.

Construction of a circRNA-miRNA-mRNA Network Related to Macrophage Infiltration in Hepatocellular Carcinoma

“…Among the six hub DEmRNAs, EZH2 has been demonstrated to be highly expressed in HCC, and injection of EZH2 inhibitor GSK126 induces CXCL10 production from macrophages and causes plasma cell polarization, inhibition of the antitumor T cell response, and hepatoma growth (Wei et al, 2019). Additionally, inhibition of EZH2 is also able to affect the macrophage activity in some other cancer types, such as suppressing macrophage infiltration in lung cancer and shifting microglia toward the M1 phenotype in glioblastoma (Yin et al, 2017;Xia et al, 2019). Although the role of DTL, PRC1, KIF4A, ITGA6, and LAMC1 in the regulation of HCC-related macrophages remains unknown, the findings of the mentioned hub DEmRNAs in the regulation of macrophage activity in other diseases may provide the clues for HCC.…”

EZH2: a novel target for cancer treatment

“…Human lung cancer cell lines-A549 and A129L cells were transfected with shRNA, migration ability was determined by wound healing assay and invasion ability was determined by transwell assay, and the results showed that knockdown of EZH2 markedly decreased migration and invasion ability of A549 and A129L cells. Besides, matrix-metalloproteinases (MMPs), which were closely related to the cancer cells invasion and metastasis, were downregulated by EZH2 knockdown [34].…”

The CCL5/CCR5 Axis in Cancer Progression

“…Reduced tumor cell migration and invasion, suppressed metastasis and macrophage infiltration in xenografts [135] Melanoma mCCR5-Ig Increased survival of tumor-bearing mice and decreased migration and immunosuppressive potential of MDSCs [136,137] Ovarian cancer…”

“…Accordingly, miR-147-overexpressing cancer cells injected subcutaneously into mice inhibited tumor xenograft growth, showing reduced CCL5 expression, invasion, and decreased metastasis formation [134]. CCL5 is modulated at the epigenetic level by EZH2 (enhancer of zeste homolog 2) gene [135]. In vitro, EZH2 knockdown in lung cancer cells decreased CCL5 expression, resulting in reduced chemotaxis of macrophages.…”

“…In vitro, EZH2 knockdown in lung cancer cells decreased CCL5 expression, resulting in reduced chemotaxis of macrophages. In vivo, EZH2 knockdown reduced macrophage infiltration, leading to decreased tumor growth and metastasis formation [135]. CCR5 expression in lung cancer was associated with immune cell infiltration and better overall survival [175].…”