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.