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ALKBH1-mediated m¹ A demethylation of METTL3 mRNA promotes the metastasis of colorectal cancer by downregulating SMAD7 expression.

ABSTRACT: Colorectal cancer (CRC) is one of the most common malignancies, and the main cause of death from CRC is tumor metastasis. m¹ A RNA modification plays critical role in many biological processes. However, the role of m¹ A modification in CRC remains unclear. Here, we find that the m¹ A demethylase alkB homolog 1, histone H2A dioxygenase (ALKBH1) is overexpressed in CRC and is associated with metastasis and poor prognosis. Upregulation of ALKBH1 expression promotes CRC metastasis in vitro and in vivo. Mechanistically, knockdown of ALKBH1 results in a decrease in methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit (METTL3) expression, probably due to m¹ A modification of METTL3 mRNA, followed by m⁶ A demethylation of SMAD family member 7 (SMAD7) mRNA. In addition, downregulation of SMAD7 establishes an aggressive phenotype. More importantly, the cell migration and invasion defects caused by ALKBH1 depletion or METTL3 depletion are significantly reversed by SMAD7 silencing. Considering these results collectively, we propose that ALKBH1 promotes CRC metastasis by destabilizing SMAD7 through METTL3.

SUBMITTER: Chen W

PROVIDER: S-EPMC9892827 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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ALKBH1-mediated m1 A demethylation of METTL3 mRNA promotes the metastasis of colorectal cancer by downregulating SMAD7 expression.

Chen Wenwen W Wang Hao H Mi Shuyi S Shao Liming L Xu Zhipeng Z Xue Meng M

Molecular oncology 20221230 2

Colorectal cancer (CRC) is one of the most common malignancies, and the main cause of death from CRC is tumor metastasis. m1 A RNA modification plays critical role in many biological processes. However, the role of m1 A modification in CRC remains unclear. Here, we find that the m1 A demethylase alkB homolog 1, histone H2A dioxygenase (ALKBH1) is overexpressed in CRC and is associated with metastasis and poor prognosis. Upregulation of ALKBH1 expression promotes ...[more]

PMID: 36550779

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Project description:Simple Summary Colorectal cancer (CRC) is the third leading cause of cancer deaths worldwide, and no cure exists for most patients at advanced stages with distant metastasis. CircUHRF2 has been aberrantly expressed in CRC, but its role in CRC growth and metastasis remains largely unclear. This study demonstrated that circUHRF2 was upregulated in CRC and correlated with poor prognostic outcomes in CRC patients. Methyltransferase-like 3 (METTL3) facilitated circUHRF2 expression through N6-methyladenine modification (m6A) modification. circUHRF2 or METTL3 silencing suppressed in vitro cell stemness, migration, and invasion; and in vivo tumor growth and liver metastasis. Furthermore, circUHRF2 is bound with insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) and increases the stability and expression of DEAD-box helicase 27 (DDX27) mRNA. Anti-cancer effect of circUHRF2 silencing was counteracted by DDX27 overexpression. Our identification of the oncogenic roles of circUHRF2 and METTL3 in CRC progression as well as their regulatory function through the IGF2BP1-DDX27 axis, has broadened our current knowledge about CRC and may help the future development of more efficient treatments. Abstract Increasing evidence has implicated that circular RNAs (circRNAs) exert important roles in colorectal cancer (CRC) occurrence and progression. However, the role of a novel circRNA, circUHRF2, remains unknown in CRC. Our work aimed at identifying the functional roles of circUHRF2 in CRC and illustrating the potential mechanisms. As assessed by quantitative real-time PCR (qRT-PCR), circUHRF2 and methyltransferase-like 3 (METTL3) were highly expressed in CRC specimens and cells. Sanger sequencing and RNase R assays were performed to verify the ring structure of circUHRF2. Notably, aberrantly increased expression of circUHRF2 was positively correlated with poor prognosis of CRC patients. Functional experiments indicated that CRC stemness, migration, and epithelial-mesenchymal transition (EMT) were suppressed by the knockdown of circUHRF2 or METTL3. Mechanistically, METTL3 enhanced circUHRF2 expression through N6-methyladenine (m6A) modification. Rescue experiments showed that overexpression of circUHRF2 reversed the repressive effect of METTL3 silencing on CRC progression. Moreover, circUHRF2 inhibited the loss of DEAD-box helicase 27 (DDX27) protein via promoting the interaction between insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) and DDX27 mRNA. DDX27 knockdown repressed CRC malignant properties, which was counteracted by circUHRF2 overexpression. The in vivo assays in nude mice demonstrated that circUHRF2 or METTL3 silencing exerted a suppressive effect on CRC growth and liver metastasis via repressing DDX27 protein expression. Taken together, METTL3-mediated m6A modification upregulated circUHRF2 and subsequently inhibited loss of DDX27 protein via recruitment of IGF2BP1, which conferred CRC stemness and metastasis. These findings shed light on CRC pathogenesis and suggest circUHRF2 as a novel target for CRC treatment.

Dataset Information

ALKBH1-mediated m¹ A demethylation of METTL3 mRNA promotes the metastasis of colorectal cancer by downregulating SMAD7 expression.

Publications

ALKBH1-mediated m<sup>1</sup> A demethylation of METTL3 mRNA promotes the metastasis of colorectal cancer by downregulating SMAD7 expression.

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