Dysregulated epigenetic and transcriptional programming due to abnormalities of
transcription factors (TFs) contributes to and sustains the oncogenicity of
cancer cells. Here, we unveiled the role of zinc finger
protein 280C (ZNF280C), a known DNA damage response
protein, as a tumorigenic TF in
colorectal cancer (CRC), required for
colitis-associated
carcinogenesis and Apc deficiency–driven intestinal
tumorigenesis in mice. Consistently, ZNF280C silencing in human CRC cells inhibited proliferation, clonogenicity, migration, xenograft growth, and liver
metastasis. As a C2H2 (Cys2-His2) zinc finger-containing TF, ZNF280C occupied genomic intervals with both transcriptionally active and repressive states and coincided with
CCCTC-binding factor (CTCF) and
cohesin binding. Notably, ZNF280C was crucial for the repression program of trimethylation of
histone H3 at
lysine 27 (H3K27me3)-marked genes and the maintenance of both focal and broad H3K27me3 levels. Mechanistically, ZNF280C counteracted CTCF/
cohesin activities and condensed the
chromatin environment at the cis elements of certain tumor suppressor genes marked by H3K27me3, at least partially through recruiting the epigenetic repressor structural maintenance of chromosomes flexible hinge domain-containing 1 (SMCHD1). In clinical relevance, ZNF280C was highly expressed in primary
CRCs and distant
metastases, and a higher ZNF280C level independently predicted worse prognosis of CRC patients. Thus, our study uncovered a contributor with good prognostic value to CRC pathogenesis and also elucidated the essence of
DNA-binding TFs in orchestrating the epigenetic programming of gene regulation.