SUMOylation of methyltransferase-like 3 facilitates colorectal cancer progression by promoting circ_0000677 in an m6 A-dependent manner

Abstract

Background and aim: Colorectal cancer (CRC) is one of the major health issues in the world. Circ_0000677 has been shown to be upregulated in CRC with unclarified function and mechanism. Methyltransferase-like 3 (METTL3) acts as a regulator for gene expression via the mechanism of RNA N⁶ -methyladenosine (m⁶ A) in different types of cancer, which is under the control of SUMO1-based SUMOylation. We aim to investigate their roles in CRC progression.

Methods: Quantitative real-time polymerase chain reaction and Western blot were used to detect the expressions of METTL3, circ_0000677, and ATP binding cassette subfamily c member 1(ABCC1) in CRC patients' tissues and cell lines. The functions of ABCC1 and circ_0000677 in CRC were studied by manipulating their level via knocking down or overexpression. RNA pull-down and RNA immunoprecipitation assays were performed to identify the specific binding of target genes. The biological function of SUMOylation of METTL3 was investigated in vivo by xenograft mice tumor model.

Results: METTL3, circ_0000677, and ABCC1 were upregulated in CRC patients' samples and cell lines. Circ_0000677 positively regulates CRC cell proliferation and drug resistance via affecting ABCC1 expression. METTL3 facilitated circ_0000677 level via m⁶ A modification. METTL3 was regulated by SUMO1-mediated SUMOylation in CRC. Mutation of METTL3-K459 could suppress tumor growth in vivo via regulating circ_0000677/ABCC1 axis.

Conclusions: Overall, our study revealed that circ_0000677 and its downstream target ABCC1 were upregulated in CRC cells, induced by the METTL3-mediated m⁶ A modification of circ_0000677 and SUMO1-mediated SUMOylation of METTL3. This work provided a new strategy for the therapeutic treatment of CRC.

Keywords: ATP Binding Cassette Subfamily C Member 1; Circ_0000677; Colorectal cancer; Methyltransferase-like 3; SUMO1.