The role of m⁶A-rna methylation in bladder cancer development, progression, and treatment response

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Abstract

Bladder cancer (BCa) remains a significant clinical challenge, characterized by high recurrence rates and variable responses to immunotherapy and chemotherapy. Recent studies have highlighted the role of N6-methyladenosine (m⁶A) RNA modification in regulating various cellular processes, including tumor progression and drug resistance. This review examines the impact of m⁶A methylation on BCa pathogenesis, with a particular focus on the role of m⁶A pathway factors and m⁶A-modified RNAs in tumorigenesis, proliferation, invasion and migration processes. Moreover, mechanisms of m⁶A-mediated chemotherapeutic resistance in BCa cells are evaluated, including single nucleotide polymorphisms in m⁶A-associated patterns. Significant advances in high-throughput analysis of m⁶A methylation enabled development of novel m⁶A-based biomarkers for risk assessment and early diagnosis of BCa, prediction of cancer relapse, and treatment response. In this manuscript, the prospects of m⁶A-based molecular diagnostics in BCa are outlined.

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About the authors

T. V. Sinyagovskaya

First Moscow State Medical University (Sechenov University)

Author for correspondence.
Email: tsv.relentless@gmail.com

Laboratory of Genetic Technologies, Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases

Russian Federation, 119991 Moscow

Yu. A. Li

First Moscow State Medical University (Sechenov University)

Email: tsv.relentless@gmail.com

Institute for Urology and Reproductive Health

Russian Federation, 119991 Moscow

N. S. Vinchevskaya-Khmelnitskaya

First Moscow State Medical University (Sechenov University)

Email: tsv.relentless@gmail.com

Institute for Urology and Reproductive Health

Russian Federation, 119991 Moscow

A. M. Agabalaeva

First Moscow State Medical University (Sechenov University)

Email: tsv.relentless@gmail.com

Institute for Urology and Reproductive Health

Russian Federation, 119991 Moscow

N. I. Ponomareva

First Moscow State Medical University (Sechenov University)

Email: tsv.relentless@gmail.com

Laboratory of Genetic Technologies, Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases

Russian Federation, 119991 Moscow

S. A. Brezgin

First Moscow State Medical University (Sechenov University)

Email: tsv.relentless@gmail.com

Laboratory of Genetic Technologies, Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases

Russian Federation, 119991 Moscow

I. A. Goptar

First Moscow State Medical University (Sechenov University)

Email: tsv.relentless@gmail.com

Laboratory of Genetic Technologies, Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases

Russian Federation, 119991 Moscow

V. P. Chulanov

First Moscow State Medical University (Sechenov University); Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: tsv.relentless@gmail.com

Department of Infectious Diseases

Russian Federation, 119991 Moscow; 119991 Moscow

A. M. Dymov

First Moscow State Medical University (Sechenov University)

Email: tsv.relentless@gmail.com

Institute for Urology and Reproductive Health

Russian Federation, 119991 Moscow

A. Z. Vinarov

First Moscow State Medical University (Sechenov University)

Email: tsv.relentless@gmail.com

Institute for Urology and Reproductive Health

Russian Federation, 119991 Moscow

D. S. Kostyushev

First Moscow State Medical University (Sechenov University)
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: tsv.relentless@gmail.com

Laboratory of Genetic Technologies, Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, Faculty of Bioengineering and Bioinformatics

Russian Federation, 119991 Moscow; 119991 Moscow

A. P. Kostyusheva

First Moscow State Medical University (Sechenov University)

Email: tsv.relentless@gmail.com

Laboratory of Genetic Technologies, Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases

Russian Federation, 119991 Moscow

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2. Fig. 1. Oncogenic effect of m⁶A-modification of RNA in bladder cancer biology. a – m⁶A-methylation of ITGA6 mRNA in bladder cancer, associated with METTL3 activity and the “reader” proteins YTHDF1 and YTHDF3, enhances transcript translation and promotes tumor progression [55]. b – The METTL3–m⁶A–CDCP1 pathway regulates CDCP1 expression and translation in bladder cancer, promoting tumor progression, migration, and metastasis [63]. c – FTO demethylase (m⁶A “eraser” enzyme) regulates the expression and stability of PTPN6, encoding a key phosphatase involved in signaling pathways and cancer progression, indicating its potential use as a prognostic biomarker in bladder cancer [42]. g – In BC, NRF2 promotes tumor growth and development of resistance to ferroptosis via m⁶A-mediated transcript stabilization with the participation of WTAP and YTHDF1 [92]. d – FTO plays an oncogenic role in BC by reducing the level of m⁶A-methylation of MALAT1 lncRNA, increasing its stability and expression levels. This, in turn, stimulates tumor growth via the miR-384 “sponge” mechanism and an increase in MAL2 levels; higher FTO expression correlates with more advanced stages of BC [43]. e – IGF2BP2 stabilizes the m⁶A-modified NRP1 transcript, which leads to polarization of macrophages to the M2 type and promotes BC progression [46]. g – FTO enhances cancer progression by regulating pri-miR-576 maturation in a m⁶A-dependent manner, affecting the miR-576–CDK6 pathway; increased FTO expression correlates with more advanced stages of the tumor process [44]. h – In cancer, METTL3 increases miRNA-221/222 maturation through m⁶A modification, enhancing cancer progression by inhibiting the tumor suppressor gene PTEN [99]. i – METTL14 promotes cancer progression by increasing lncDBET expression, which activates the PPAR signaling pathway and alters lipid metabolism through interaction with FABP5 [103]. k – In cancer, m⁶A-methylated circPSMA7 is stabilized by IGF2BP3, enhancing MAPK1 mRNA stability and promoting tumor progression; miR-128-3p is able to reverse this effect [102]. l – IGF2BP3 interacts with HMGB1 via m⁶A modification, influencing the immune microenvironment in BC and the efficacy of immunotherapy; high levels of IGF2BP3 are associated with poor prognosis [47]

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3. Fig. 2. Anti-oncogenic effect of m⁶A-modification of RNA in bladder cancer biology. a – The METTL14–m⁶A–NOTCH1 pathway in bladder cancer suppresses tumor cell self-renewal [71]. b – SYTL1 enhances the antitumor immune response through NK cell activation, but its expression is reduced due to WTAP-dependent m⁶A-methylation, which leads to transcript degradation via YTHDF2 [81]. c – METTL3-dependent m⁶A-modification of tumor suppressor factor SETD7 mRNA, recognized by YTHDF2, leads to mRNA degradation [80]. d – KLF4 (tumor suppressor) is weakly expressed in bladder cancer cells and is associated with low survival and the risk of relapse; when overexpressed, KLF4 inhibits cell proliferation and induces cell cycle arrest in the G1 phase. METTL3 carries out m⁶A-methylation of KLF4 mRNA, which leads to mRNA degradation via the YTHDF2 reader protein [80]. d – LINC01106 stabilizes DAB1 mRNA, which is associated with more favorable prognoses in BC, while miR-3148 inhibits DAB1 mRNA translation, which is associated with unfavorable outcomes in BC. CRISPR-mediated hypermethylation of LINC01106 increases its affinity for DAB1 mRNA [101]

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4. Fig. 3. Scheme of personalized treatment strategy based on profiling of m⁶A RNA modifications. a – Obtaining biomaterial from patients with bladder cancer. Identification of m⁶A with assessment of m⁶A methylation patterns. b – Division of patients into different subgroups depending on m⁶A profiles. c – Compilation of m⁶A patient map with assessment of the stage and characteristics of the disease, the possibility of using therapeutic approaches taking into account drug resistance profiles, with prognosis of disease progression and patient survival based on m⁶A profiles. d – Development of a personalized treatment strategy for patients based on multiparametric analysis of m⁶A profiles

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