CMTR1 promotes colorectal cancer cell growth and immune evasion by transcriptionally regulating STAT3

CMTR1, also called IFN-stimulated gene 95 kDa protein (ISG95), is elevated by viral infection in a variety of cells. However, the function of CMTR1 in colorectal cancer (CRC), especially its role in tumorigenesis and immune regulation, remains unclear. Here, we first identified CMTR1 as a novel oncogene in colorectal cancer. Based on The Cancer Genome Atlas (TCGA) database exploration and human tissue microarray (TMA) analysis, we found that CMTR1 expression was markedly higher in colorectal cancer tissues compared to that in adjacent normal tissues. High CMTR1 was correlated with poor prognosis of colorectal cancer patients. Knockdown (KD) of CMTR1 significantly suppressed cell proliferation and tumorigenicity both in vitro and in vivo, whereas overexpression of CMTR1 exhibited the opposite effects. KEGG analysis revealed that the JAK/STAT signaling pathway was differentially enriched in colorectal cancer cells with CMTR1 KD. Mechanistically, repression of CMTR1 inhibited RNAPII recruitment to the transcription start site (TSS) and repression of STAT3 expression and activation. Furthermore, PD1 blockade immunotherapy was prominently enhanced with CMTR1 KD by increased infiltration of CD8+ T cells into tumor microenvironment. Overall, it appears that CMTR1 plays a key role in regulating tumor cell proliferation and antitumor immunity.