Targeting m7G-enriched circKDM1A prevents colorectal cancer progression

Area of Science:

• Molecular Biology
• Oncology
• RNA Biology

Background:

• Circular RNAs (circRNAs) are implicated in colorectal cancer (CRC), but the mechanisms driving their aberrant expression remain unclear.
• RNA modifications, such as N6-methyladenosine (m6A), are increasingly recognized for their roles in gene regulation and cancer.

Purpose of the Study:

• To investigate the role of m7G RNA modifications in circRNAs within colorectal cancer.
• To elucidate the mechanism by which METTL1 influences circRNA stability and CRC progression.
• To identify specific circRNAs regulated by METTL1 and their downstream effects on CRC.

Main Methods:

• Analysis of m7G modification enrichment in circRNAs from CRC samples.
• Identification of METTL1 as the m7G methyltransferase for circRNAs, with GG motif preference.
• Functional assays (in vitro and in vivo) to assess the impact of circKDM1A and its m7G modification on CRC cell proliferation, invasion, and migration.
• Western blotting and qRT-PCR to examine the activation of the AKT pathway and PDK1 expression.

Main Results:

• m7G modifications are enriched in certain circRNAs in CRC, catalyzed by METTL1 with a preference for the GG motif.
• METTL1 promotes CRC progression by stabilizing circKDM1A via m7G modification, enhancing proliferation, invasion, and migration.
• CircKDM1A activates the AKT pathway by upregulating PDK1, thereby promoting CRC progression; this effect is diminished upon m7G site mutation.

Conclusions:

• METTL1-mediated m7G modification of circRNAs is a crucial mechanism in colorectal cancer progression.
• The identified circKDM1A acts as an oncogene in CRC by stabilizing through m7G modification and activating the AKT/PDK1 pathway.
• This study uncovers a novel regulatory axis involving METTL1, m7G-modified circRNAs, and the AKT pathway in CRC pathogenesis.