FBW7 suppresses ovarian cancer development by targeting the N6-methyladenosine binding protein YTHDF2

Abstract

Background The tumor suppressor FBW7 is the substrate recognition component of the SCF E3-ubiquitin ligase complex that mediates proteolytic degradation of various oncogenic proteins. However, the role of FBW7 in ovarian cancer progression remains inadequately understood. Methods IP-MASS, co-IP, immunohistochemistry, and western blotting were used to identify the potential substrate of FBW7 in ovarian cancer. The biological effects of FBW7 were investigated using in vitro and in vivo models. LC/MS was used to detect the m6A levels in ovarian cancer tissues. MeRIP-Seq and RNA-Seq were used to assess the downstream targets of YTHDF2. Results We unveil that FBW7 is markedly down-regulated in ovarian cancer tissues and its high expression is associated with favorable prognosis and elevated m6A modification levels. Consistently, ectopic FBW7 inhibits ovarian cancer cell survival and proliferation in vitro and in vivo, while ablation of FBW7 empowers propagation of ovarian cancer cells. In addition, the m6A reader protein, YTHDF2, is identified as a novel substrate for FBW7. FBW7 counteracts the tumor-promoting effect of YTHDF2 by inducing proteasomal degradation of the latter in ovarian cancer. Furthermore, YTHDF2 globally regulates the turnover of m6A-modified mRNAs, including the pro-apoptotic gene BMF. Conclusions Our study has demonstrated that FBW7 suppresses tumor growth and progression via antagonizing YTHDF2-mediated BMF mRNA decay in ovarian cancer.

Integrative bioinformatics and experimental analysis revealed down-regulated CDC42EP3 as a novel prognostic target for ovarian cancer and its roles in immune infiltration

“…In addition, Huang et al disclosed that the fat mass- and obesity-associated protein (FTO), an m 6 A demethylase, was down-regulated in ovarian cancer stem cells (CSC) and inhibited the cell self-renewal by blocking cAMP signaling ( Huang et al, 2020b ). Xu and the colleague revealed that F-box and WD repeat domain-containing 7 (FBW7) suppressed ovarian cancer progression through targeting the m 6 A binding protein YTH domain family 2 (YTHDF2) ( Xu et al, 2021 ). Nevertheless, more research should be carried out to clarify the detailed mechanisms of m 6 A modification in ovarian tumorigenesis and development.…”

The m6A RNA Modification Quantity and mRNA Expression Level of RNA Methylation-Related Genes in Head and Neck Squamous Cell Carcinoma Cell Lines and Patients

“…Accumulating data indicates the significant role of m 6 A RNA modification in the post-transcriptional regulation of gene expression that determines the proper function of crucial physiological processes. Therefore, disturbances in m 6 A RNA methylation may lead to the development of pathological changes, including cancers [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. HNSCC initiation, progression, and growth are complex molecular processes encompassing genetic and epigenetic alterations.…”

“…However, to the best of our knowledge, we have determined for the first time the m 6 A modification level in four HNSCC cell lines. To date, a similar m 6 A quantification method was used in ovarian cancer studies that also showed no differences between ovarian cancer and normal tissues but indicated a correlation between its elevated content with patients’ overall survival [ 21 ]. In the case of pancreatic cancer, the higher level of m 6 A modification measured using HPLC/MS was also correlated with patients’ overall survival and with more lymphatic metastases [ 22 ].…”

“…YTHDF2 binding to m 6 A promotes RNA decay, while YTHDC2 is involved in mRNA degradation and translation initiation. These regulators were demonstrated to play a crucial role in a variety types of cancers [ 21 , 30 , 31 , 32 ]. The role of the YTHDF2 gene in HNSCC has not been explored so far, whereas YTHDC2 was found to be a tumor suppressor with low expression in HNSCC samples, while its upregulation was associated with longer-term survival and the recurrence-free survival of HNSCC patients [ 33 ].…”

Emerging role of m6A methylation modification in ovarian cancer

“…In OC studies, m6A modification research mainly focuses on YTH domain family members (YTHDF1 and YTHDF1) and insulin-like growth factor 2 mRNA-binding proteins (IGF2BP1) [ 40 , 80 – 82 , 112 ]. Through functional and experimental analyses of ovarian cancer, recent studies underscore the protumour role of m6A ‘readers’ in vitro and in vivo, with regard to tumour growth, invasion and CSC phenotype [ 40 , 80 – 82 , 112 ] (Table 3 ).…”