Colorectal cancer (CRC) stem cells are resistant to cancer therapy and are therefore responsible for tumour progression after conventional therapy fails. However, the molecular mechanisms underlying the maintenance of stemness are poorly understood. In this study, we identified PCGF1 as a crucial epigenetic regulator that sustains the stem cell-like phenotype of CRC. PCGF1 expression was increased in CRC and was significantly correlated with cancer progression and poor prognosis in CRC patients. PCGF1 knockdown inhibited CRC stem cell proliferation and CRC stem cell enrichment. Importantly, PCGF1 silencing impaired tumour growth in vivo.
FIG: PCGF1 is upregulated in colorectal cancer:A Expression of PCGF1 in different types of tumours in the GEDS database. The red boxes refer to colorectal READ and COAD. B Expression of PCGF1-6 in colorectal cancer in the GEPIA database. COAD (num(T) = 275; num(N) = 41), READ (num(T) = 92; num(N) = 10). T, tumour; N, normal. C PCGF1 expression levels in specimens with various clinical stages. D Kaplan–Meier analyses of the OS rate in CRC patients in the GEPIA database with high or low expression of PCGF1 (n = 135, log-rank test). The hazard ratio (HR) and P value (log-rank test) for each comparison are shown.
Mechanistically, PCGF1 bound to the promoters of CRC stem cell markers and activated their transcription by increasing the H3K4 histone trimethylation (H3K4me3) marks and decreasing the H3K27 histone trimethylation (H3K27me3) marks on their promoters by increasing expression of the H3K4me3 methyltransferase KMT2A and the H3K27me3 demethylase KDM6A. Our findings suggest that PCGF1 is a potential therapeutic target for CRC treatment.
Ji, G., Zhou, W., Du, J. et al. PCGF1 promotes epigenetic activation of stemness markers and colorectal cancer stem cell enrichment. Cell Death Dis 12, 633 (2021). https://doi.org/10.1038/s41419-021-03914-2