MTHFR inhibits TRC8‐mediated HMOX1 ubiquitination and regulates ferroptosis in ovarian cancer

Abstract

Dear Editor,The study is the first to confirm that methylenetetrahydrofolate reductase (MTHFR) could inhibit HMOX1 ubiquitination degradation by competitive interaction with TRC8, followed by blocking the occurrence of ferroptosis in ovarian cancer (OV) cells, and promote the tumour cells growth. OV attributes to the world's second most familiar cause of gynaecologic cancer death. 1 Recent research studies identified that the polymorphisms of MTHFR correlate with the risk of common gynaecological cancers. 2,3 However, there is a dearth of studies with in-detail elucidation of functions and mechanisms of MTHFR in OV.MTHFR is a key enzyme involved in folic acid metabolism. 2 In this study, it was found that MTHFR was upregulated in OV cell lines (SKOV3, TOV112D, A2780 and OVCAR3) and tissues both in mRNA and protein levels (Figures 1A,B and S1A). The mRNA and protein expression of MTHFR was found to be higher in A2780 and OVCAR3 cells, which led us to the selection of A2780 and OVCAR3 cells for further study. The higher expression of MTHFR was associated with poor overall survival (OS), progression-free survival (PFS) and post-progression survival (Figure S1B-D). As shown in Figures 1C-F and S2A-C, it was found that the colony numbers and cell viability were obviously decreased in MTFHR-interfering cells compared to the control cells, as determined by the colony formation and CCK8 assays, respectively. In addition, we applied a lentivirus-medicated expression system to stably overexpress MTHFR in MTFHR-interfered OV cells (Figures 1G and S2D). By colony formation and CCK8 assays, the overexpression of MTHFR significantly reversed the inhibition effects of MTHFR knock-down in OV cells F). Cisplatin, cisplatinum or cis-diamminedichloroplatinum(II) (CDDP) are a classical antitumour drug, which could be considered an inducer for ferroptosis. 4,5 Moreover, the expression of MTHFR in OV cells was decreased in a dose-dependent manner of CDDP (Figure S3A,B). Interestingly, the con-Xiang Wang and Zhijie Xu made equal contributions to this work.

OTUD3 suppresses the mTORC1 signaling by deubiquitinating KPTN

“…Ubiquitination modification has long been an area of keen interest for researchers, especially in the field of protein regulation ( Wang et al, 2022 ; Zhang et al, 2023b ). The discovery that ubiquitination targets proteins for proteasomal degradation earned the Nobel Prize in Chemistry in 2004.…”

FHOD1 is upregulated in glioma cells and attenuates ferroptosis of glioma cells by targeting HSPB1 signaling

“…And this study has been approved by the Ethical Committee of Xiangya Hospital, Central South University. The immunohistochemistry (IHC) analysis was conducted as previously described 21,22 . In brief, the IHC Select® HRP/DAB kit (Millipore, # DAB150) was used to conduct the immunohistochemical staining of FHOD1 (1:150) and HSPB1 (1:150).…”

Targeting one‐carbon metabolism for cancer immunotherapy

“…MTHFR is the rate-limiting enzyme that catalyses the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. 76,77 A study showed that increasing the concentration of unmetabolised folic acid could decrease the number and cytotoxicity of NK cells. 78 In addition, the polymorphisms of MTHFR could influence the regulation of immune cells.…”