Aberrant epigenetic regulation of FZD3 by TET2 is involved in ovarian cancer cell resistance to cisplatin

摘要

A major challenge in platinum-based cancer therapy, including cisplatin (DDP), is the clinical management of chemo-resistant tumours, which have unknown pathogenesis at the level of epigenetic mechanism. To identify potential resistance mechanisms, we integrated ovarian cancers (OC)-related GEO database retrieval and prognostic analyses. The results of bioinformatics prediction showed that frizzled class receptor 3 (FZD3) was a DDP-associated gene and closely related to the prognosis of OC. DDP resistance in OC inhibited FZD3 expression. FZD3 reduced DDP resistance in OC cells, increased the inhibitory effect of DDP on the growth and aggressiveness of DDP-resistant cells, and promoted apoptosis and DNA damage. TET2 was reduced in OC. TET2 promoted the transcription of FZD3 through DNA hydroxymethylation. TET2 sensitized the drug-resistant cells to DDP in vitro and in vivo, and the ameliorating effect of TET2 on drug resistance was significantly reversed after the inhibition of FZD3. Our findings reveal a previously unknown epigenetic axis TET2/FZD3 suppression as a potential resistance mechanism to DDP in OC.

关键词