P-250 A novel small molecule inhibits enzyme associated with colorectal cancer

Abstract

Colorectal cancer (CRC) represents one of the most common malignant tumor with high morbidity worldwide. N6-methyladenosine (m6A) methylation, is the most frequently observed RNA modifications that tremendously contribute to cancer initiation, progression, and resistance. METTL3 (Methyltransferase like 3), is a predominant catalytic enzyme in the m6A methyltransferase system. METTL3 has been implicated in carcinogenesis in various cancers including colon cancer by stabilizing oncogenic mRNAs in an m6A-dependent manner which is why it is considered as an attractive target for cancer therapy. Here, we identified STM2457, as a selective small-molecule METTL3 inhibitor that exerts promising anticancer activity in CRC. We detected the mRNA and protein expression of METTL3 and its target oncogenes in human colorectal cancer cell line panel. The anti-tumor activities of STM2457 in human colorectal cancer cell line panel were investigated by MTT, wound healing, colony formation, western blot assays, and 3D spheroid model. m6A level of mRNA was measured by an m6A-RNA methylation quantification kit. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) was used to screen the target genes of METTL3. We discovered that STM2457 treatment exerted potential anticancer effects in CRC cells. Pharmacological inhibition of METTL3 by STM2457 reduced cellular proliferation, invasion, colony formation, and tumorsphere formation of CRC cells. STM2457 treatment reduced m6A level in CRC cells. Mechanistically, MeRIP-seq illustrated that SLC2A1 (Solute Carrier Family 2 Member 1) as a target of METTL3. The TCGA data analysis showed that SLC2A1 mRNA and protein were highly expressed in colorectal cancer tissues. In addition, the highly expressed SLC2A1 mRNA associated with metastasis and poor survival in CRC patients. Thus, the METTL3/m6A/SLC2A1 axis accelerated colorectal carcinogenesis. The data show that the blockade of METTL3/m6A/SLC2A1 axis by a potent and novel small-molecule inhibitor, STM2457 is a promising approach for treatment of CRC.