MeCP2 Promotes Colorectal Cancer Metastasis by Modulating ZEB1 Transcription

Abstract

Background: Recurrence and distant organ metastasis is a major cause of death in colorectal cancer (CRC); however, the underlying molecular mechanisms regulating this phenomenon are poorly understood. MeCP2 is a key epigenetic regulator and is amplified in many types of cancer. Its role in CRC and the molecular mechanisms underlying its action remain unknown. Methods: We used western blot and immunohistochemistry to detect MeCP2 expression in CRC tissues, and then investigated its biological functions in vitro and in vivo. Chromatin immunoprecipitation, co-immunoprecipitation, and electrophoretic mobility shift assays were used to detect the associations among MeCP2 (Methyl-CpG binding protein 2), SPI1 (Spi-1 Proto-Oncogene), and ZEB1 (Zinc Finger E-Box Binding Homeobox 1). Results: Using the Cancer Genome Atlas and Oncomine databases, we found MeCP2 expression was upregulated in CRC tissues and this upregulation was related to poor prognosis. Meanwhile, MeCP2 depletion (KO/KD) in CRC cells significantly inhibited stem cell frequency, and invasion and migration ability in vitro, and suppressed CRC metastasis in vivo. Mechanistically, we show MeCP2 binds to the transcription factor SPI1, and aids its recruitment to the ZEB1 promoter. SPI1 then facilitates ZEB1 expression at the transcription level. In turn, ZEB1 induces the expression of MMP14, CD133, and SOX2, thereby maintaining CRC stemness and metastasis. Conclusions: MeCP2 is a novel regulator of CRC metastasis. MeCP2 suppression may be a promising therapeutic strategy in CRC.

Methyl CpG binding protein 2 promotes colorectal cancer metastasis by regulating N6‐methyladenosine methylation through methyltransferase‐like 14

“…Although recent experimental evidence has shown that MeCP2 contributes to cancer proliferation and metastasis, 31,46,47 the biological mechanism of MeCP2 on carcinogenesis is still unclear.…”

“…Although recent experimental evidence has shown that MeCP2 contributes to cancer proliferation and metastasis, 31,46,47 the biological mechanism of MeCP2 on carcinogenesis is still unclear. Here, we found a novel mechanism through indirect influence on m 6 A methylation modification.…”

“…Recently, some studies have revealed MeCP2 as an oncogene in CRC. 9,31 To further determine the biological roles of MeCP2 in CRC, we detected the protein and mRNA expression of MeCP2 in six CRC cell lines (Figure S1). Then shRNA was used to knock down MeCP2 in HT29, HCT8, and SW620 cells (Figures 2A,B and S2G).…”

Shared and disease-specific host gene-microbiome interactions across human diseases

“…We identified 87 host pathways that are unique to each disease, including 22 CRC-specific, 60 IBD-specific, and 5 IBS-specific pathways that interact with unique gut bacteria, of which we visualized top 10 most significant host pathways per disease ( Figure 3B , Fisher’s exact test, Benjamini-Hochberg FDR < 0.2, Supplementary Table S9, see Methods). The host pathways enriched for CRC-specific interactions are known to modulate tumor growth, progression and metastasis in CRC, such as Interleukin-10 signaling, signaling by NOTCH1 in cancer, and regulation of MECP2 expression and activity 63–66 . The host pathways we identified as enriched for IBD-specific interactions are known to be responsible for maintenance of gastric mucosa integrity, inflammatory response, and host defence against invading pathogens, such as thrombin signalling through proteinase activated receptors (PARs), and glucagon type ligand receptors 67,68 .…”

Laryngeal Squamous Cell Carcinoma: Potential Molecular Mechanism and Prognostic Signature Based on Immune-Related Genes

“…SPI1 , SP140 , and STAT4 were likely to be key TRs regulating up-IRDEGs; ZEB1 and IKZF2 may be the important TRs regulating down-IRDEGs. Although in previous studies, SPI1 [ 54 ] and STAT4 [ 55 ] have been identified as influencing tumors, insight into the regulatory mechanisms of these 5 TRs in LSCC is limited in the literature and more research is needed to verify their role.…”