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

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.

Automated summary

A major challenge in platinum-based cancer therapy is the management of chemo-resistant tumors, which have unknown epigenetic mechanisms. By analyzing ovarian cancer databases, we found that FZD3, a transmembrane receptor protein, is associated with cisplatin (DDP) resistance and the prognosis of ovarian cancer. Inhibition of FZD3 expression enhances DDP resistance, while TET2 promotes FZD3 transcription through DNA hydroxymethylation. TET2 sensitizes drug-resistant cells to DDP, and its effect is reversed after inhibiting FZD3.