Fisetin decreases TET1 activity and CCNY/CDK16 promoter 5hmC levels to inhibit the proliferation and invasion of renal cancer stem cell.

ABSTRACT

As a natural flavonol, fisetin has significant inhibitory effects on many cancers. Although fisetin can inhibit kidney cancer, its effects on kidney renal stem cells (HuRCSCs) remain unknown. Our study found that renal cancer tissues and CD44+/CD105+ HuRCSCs both show high TET1 protein expression. Both in vivo and in vitro experiments showed that fisetin can effectively inhibit HuRCSC cell division and proliferation, invasion, in vivo tumourigenesis and angiogenesis. Our findings showed that fisetin can significantly decrease TET1 expression levels in HuRCSCs and overall 5hmC levels in the genomes of these cells. At the same time, ChIP-PCR results showed that fisetin can effectively inhibit 5hmC modification levels at the CpG islands in cyclin Y (CCNY) and CDK16 and reduce their transcription and activity. Thus, we conclude that fisetin inhibits the epigenetic mechanism in renal cancer stem cells, that is, fisetin inhibits TET1 expression and reduces 5hmC modification in specific loci in the promoters of CCNY/CDK16 in HuRSCs. This in turn inhibits transcription of these genes, causing cell cycle arrest and ultimately inhibiting renal cancer stem cell activity.