MeCP2 Promotes Colorectal Cancer Metastasis by Modulating ZEB1 Transcription
<i>Background</i>: 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. It...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-03-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/12/3/758 |
| _version_ | 1797719559625506816 |
|---|---|
| author | Dan Luo Wei Ge |
| author_facet | Dan Luo Wei Ge |
| author_sort | Dan Luo |
| collection | DOAJ |
| description | <i>Background</i>: 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. <i>Methods</i>: 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). <i>Results</i>: 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. <i>Conclusions</i>: MeCP2 is a novel regulator of CRC metastasis. MeCP2 suppression may be a promising therapeutic strategy in CRC. |
| first_indexed | 2024-03-12T09:06:34Z |
| format | Article |
| id | doaj.art-4adc92e2760f496a9a843429bc76e2bf |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T09:06:34Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-4adc92e2760f496a9a843429bc76e2bf2023-09-02T15:14:24ZengMDPI AGCancers2072-66942020-03-0112375810.3390/cancers12030758cancers12030758MeCP2 Promotes Colorectal Cancer Metastasis by Modulating ZEB1 TranscriptionDan Luo0Wei Ge1National Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, 5 Dong Dan San Tiao, Dongcheng District, Beijing 100005, ChinaNational Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, 5 Dong Dan San Tiao, Dongcheng District, Beijing 100005, China<i>Background</i>: 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. <i>Methods</i>: 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). <i>Results</i>: 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. <i>Conclusions</i>: MeCP2 is a novel regulator of CRC metastasis. MeCP2 suppression may be a promising therapeutic strategy in CRC.https://www.mdpi.com/2072-6694/12/3/758colorectal cancermetastasismecp2zeb1spi1 |
| spellingShingle | Dan Luo Wei Ge MeCP2 Promotes Colorectal Cancer Metastasis by Modulating ZEB1 Transcription Cancers colorectal cancer metastasis mecp2 zeb1 spi1 |
| title | MeCP2 Promotes Colorectal Cancer Metastasis by Modulating ZEB1 Transcription |
| title_full | MeCP2 Promotes Colorectal Cancer Metastasis by Modulating ZEB1 Transcription |
| title_fullStr | MeCP2 Promotes Colorectal Cancer Metastasis by Modulating ZEB1 Transcription |
| title_full_unstemmed | MeCP2 Promotes Colorectal Cancer Metastasis by Modulating ZEB1 Transcription |
| title_short | MeCP2 Promotes Colorectal Cancer Metastasis by Modulating ZEB1 Transcription |
| title_sort | mecp2 promotes colorectal cancer metastasis by modulating zeb1 transcription |
| topic | colorectal cancer metastasis mecp2 zeb1 spi1 |
| url | https://www.mdpi.com/2072-6694/12/3/758 |
| work_keys_str_mv | AT danluo mecp2promotescolorectalcancermetastasisbymodulatingzeb1transcription AT weige mecp2promotescolorectalcancermetastasisbymodulatingzeb1transcription |