Epigenetically modulated FOXM1 suppresses dendritic cell maturation in pancreatic cancer and colon cancer

Abstract

Forkhead box transcription factor M1 ( FOXM 1) is a proliferation‐associated transcription factor involved in tumorigenesis through transcriptional regulation of its target genes in various cells, including dendritic cells ( DC s). Although previous work has shown that FOXM 1 enhances DC maturation in response to house dust mite allergens, it is not known whether FOXM 1 affects DC maturation in the context of tumor‐specific immunity. In this study, we examined the central role of FOXM 1 in regulating bone marrow‐derived dendritic cell ( BMDC ) maturation phenotypes and function in pancreatic cancer and colon cancer. FOXM 1 retarded maturation phenotypes of BMDC s, inhibited promotion of T‐cell proliferation, and decreased interleukin‐12 ( IL ‐12) p70 in tumor‐bearing mice ( TBM ). Notably, FOXM 1 expression was epigenetically regulated by dimethylation on H3 lysine 79 (H3K79me2), a modification present in both tumor cells and BMDC s. Increased H3K79me2 enrichment was observed at the FOXM 1 promoter in both BMDC s from TBM , and in BMDC s from wild‐type mice cultured with tumor‐conditioned medium that mimics the tumor microenvironment ( TME ). Furthermore, inhibition of the H3K79 methyltransferase DOT 1L not only decreased enrichment of H3K79me2, but also downregulated expression of FOXM 1 and partially reversed its immunosuppressive effects on BMDC s. Furthermore, we found that FOXM 1 upregulated transcription of Wnt family number 5A (Wnt5a) in BMDC s in vitro ; we also observed that exogenous Wnt5a expression abrogated BMDC maturation phenotypes by inhibiting FOXM 1 and H3K79me2 modification. Therefore, our results reveal that upregulation of FOXM 1 by H3K79me2 in pancreatic cancer and colon cancer significantly inhibits maturation phenotypes and function of BMDC s through the Wnt5a signaling pathway, and thus provide novel insights into FOXM 1‐based antitumor immunotherapy.

Identification of Hub Genes Associated with Melanoma Development by Comprehensive Bioinformatics Analysis

“…It has also been shown that the FOXM1-PSMB4 axis can play a catalytic role in the proliferation and development of cervical cancer [28]. More surprisingly, FOXM1 plays a vital role in many other cancers [29][30][31][32]. In our study, FOXM1 was upregulated in tumor tissues compared to normal tissues, suggesting a signi cant correlation with melanoma.…”

Identification of Hub Genes Associated with Melanoma Development by Comprehensive Bioinformatics Analysis

“…In addition, it has been shown that the FOXM1-PSMB4 axis can play a catalytic role in the proliferation and development of cervical cancer [28]. More surprisingly, FOXM1 plays a vital role in many other cancers [29][30][31][32]. In our study, FOXM1 was upregulated in tumor tissues compared to normal tissues, suggesting a signi cant correlation with melanoma.…”

Disharmonic Inflammatory Signatures in COVID-19: Augmented Neutrophils’ but Impaired Monocytes’ and Dendritic Cells’ Responsiveness

“…Several pathways are involved in DC activation and/or tolerogenicity in both malignant and non-malignant conditions. In tumors, the dual state of both the proinflammatory and immunosuppressive microenvironment is well described [ 43 , 44 , 45 , 46 ]. Wnt5, a member of the Wnt family signaling pathway, which is wildly expressed by tumors and immune cells, activates the NFκB pathway and induces the tolerogenic phenotype via the release of IL-10 [ 44 ].…”

“…Wnt5, a member of the Wnt family signaling pathway, which is wildly expressed by tumors and immune cells, activates the NFκB pathway and induces the tolerogenic phenotype via the release of IL-10 [ 44 ]. Impaired DC functions and maturation due to Wnt5 upregulation was observed in pancreatic and colon cancer [ 46 ]. Besides tumors, Wnt5 signaling is activated in sepsis or acute respiratory distress syndrome as an initiator of the lung repair process [ 47 ].…”