YTHDF1 Promotes Bladder Cancer Cell Proliferation via the METTL3/YTHDF1–RPN2–PI3K/AKT/mTOR Axis

Abstract

N6-methyladenosine (m6A) is the most common mRNA modification and it plays a critical role in tumor progression, prognoses and therapeutic response. In recent years, more and more studies have shown that m6A modifications play an important role in bladder carcinogenesis and development. However, the regulatory mechanisms of m6A modifications are complex. Whether the m6A reading protein YTHDF1 is involved in the development of bladder cancer remains to be elucidated. The aims of this study were to determine the association between METTL3/YTHDF1 and bladder cancer cell proliferation and cisplatin resistance to explore the downstream target genes of METTL3/YTHDF1 and to explore the therapeutic implications for bladder cancer patients. The results showed that the reduced expression of METTL3/YTHDF1 could lead to decreased bladder cancer cell proliferation and cisplatin sensitivity. Meanwhile, overexpression of the downstream target gene, RPN2, could rescue the effect of reduced METTL3/YTHDF1 expression on bladder cancer cells. In conclusion, this study proposes a novel METTL3/YTHDF1–RPN2–PI3K/AKT/mTOR regulatory axis that affects bladder cancer cell proliferation and cisplatin sensitivity.

A Ferroptosis-Related lncRNAs Signature Predicts Prognosis of Colon Adenocarcinoma

“…ALKBH5 can significantly inhibit the growth of COAD by regulating ALKBH5. METTL3 knockdown enhances the anti-COAD ability of anti-PD-1 immunotherapy through the PI3K/AKT pathway in TAM [40]. In in vitro studies in nude mice, METTL3 knockdown was found to inhibit COAD migration and epithelial-mesenchymal transition (EMT) by inhibiting DDX27 expression [41].…”

YTHDF1 in Tumor Cell Metabolism: An Updated Review

“…According to database analysis, YTHDF1 is highly expressed in BLCA tissues, and is closely associated with the clinical prognosis of BLCA patients such that the mechanism of YTHDF1 in BLCA is worth investigating [ 57 ]. A novel METTL3/YTHDF1-RPN2-PI3K/AKT/mTOR regulatory axis has been reported, where the upregulation of METTL3/YTHDF1 levels enhances the stability of RPN2’s (ribophorin II) mRNA and protein [ 58 ]. RPN2 may accelerate tumor cell proliferation and the progression of BLCA by activating the notorious PI3K/AKT pathway [ 59 ].…”

“…Zhu discovered that YTHDF1 can directly enhance the expression of RPN2 in the N-oligosaccharyltransferase complex in an m6A-dependent manner, along with METTL3. RPN2, through its effect on the PI3K–AKT–mTOR pathway, promotes cisplatin resistance in bladder cancer [ 58 ]. In conditions of hypoxia or low YTHDF1 expression, patients may also develop chemotherapy-induced drug resistance through YTHDF1.…”

The current landscape of m6A modification in urological cancers

“…The m6A modification content in bladder cancer tissues was lower than that in normal tissues ( Gu et al, 2019 ), but some studies also found that the m6A modification level was increased in bladder cancer samples ( Liu et al, 2022a ), which may be related to the different sample source and small sample size. It was found in humans and animal models that METTL3 ( Cheng et al, 2019 ; Jin et al, 2019 ; Xie et al, 2020 ), FTO ( Tao et al, 2021 ; Zhou et al, 2021 ), IGF2BP1 ( Xie et al, 2021 ), IGF2BP3, YTHDF1 ( Zhu et al, 2023 ), YTHDF 2, ELAV-like protein 1 (ELAVL1), HNRNPA2B1 ( Deng et al, 2022 ) were upregulated in bladder cancer cells. In contrast, METTL14 ( Gu et al, 2019 ; Guimarães Teixeira et al, 2022 ), WTAP ( Liu et al, 2021a ), YTHDC1, YTHDF3, ZC3H13 ( Deng et al, 2022 ) were reduced in bladder cancer samples.…”

“…In bladder cancer, it has demonstrated that ALKBH5, IGFBP2-3, RBM15, RBMX, YTHDC1, and YTHDF had prognostic value ( Liu et al, 2021b ). METTL14 ( Li et al, 2021a ), YTHDC1, and WTAP ( Cui et al, 2022 ) may be protective factors for bladder cancer, the higher expressions were related to the longer overall survival of patients, while IGF2BP1-3 ( Xie et al, 2021 ), YTHDF1 ( Zhu et al, 2023 ), LRPPRC ( Cui et al, 2022 ), ALKBH5, and FTO ( Deng et al, 2022 ) were risk factors for bladder cancer. The higher the FTO expression level, the lower the overall survival rate ( Tao et al, 2021 ) and the shorter disease-free survival period ( Gao et al, 2020 , p. 42020).…”