METTL3 potentiates resistance to cisplatin through m 6 A modification of TFAP2C in seminoma

• Published in: Journal of cellular and molecular medicine Vol. 24; no. 19; pp. 11366 - 11380
• Main Authors: Wei, Jingchao, Yin, Yinghao, Zhou, Jun, Chen, Hanfei, Peng, Jingxuan, Yang, Jianfu, Tang, Yuxin
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.10.2020
• Subjects: Adenosine - analogs & derivatives; Adenosine - metabolism; Animals; Antibodies; Antigens; Apoptosis; Binding sites; Cell culture; Cell fate; Cell Line, Tumor; Cell survival; Cell Survival - drug effects; Cell Survival - genetics; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Deoxyribonucleic acid; DNA; DNA methylation; DNA repair; DNA Repair - drug effects; DNA Repair - genetics; Drug Resistance, Neoplasm - drug effects; Epigenetics; Flow cytometry; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Humans; Insulin; Laboratories; Male; Malignancy; Methylation; Methyltransferase; Methyltransferases - metabolism; Mice, Inbred BALB C; Mice, Nude; mRNA stability; N6-methyladenosine; Non-coding RNA; Protein 2C; Protein Binding - drug effects; Proteins; RNA modification; RNA Stability - drug effects; RNA Stability - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-Binding Proteins - metabolism; Seminoma; Seminoma - genetics; Seminoma - metabolism; Seminoma - pathology; Testicular Neoplasms - genetics; Testicular Neoplasms - metabolism; Testicular Neoplasms - pathology; Toxicity; Transcription Factor AP-2 - genetics; Transcription Factor AP-2 - metabolism; Tumors; Up-Regulation - drug effects; Up-Regulation - genetics; Beijing China; United States > US; China; m6A; TFAP2C; chemoresistance; seminoma; METTL3
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.15738

Testicular germ cell tumours (TGCTs) rank as the most common malignancy in men aged 20-34 years, and seminomas are the most type of TGCTs. As a crucial anti-tumour agent with explicit toxicity, cisplatin may render resistance through intertwined mechanisms, even in disease entities with high curative ratio, such as seminoma. Previously, we established cisplatin-resistant seminoma TCam-2 (TCam-2/CDDP) cells and showed that epigenetic regulations, such as non-coding RNA (ncRNA) interactions, might orchestrate cell fate decisions in the cisplatin treatment context in seminoma. N6-methyladenosine (m6A) is the most prevalent internal modification in mRNA. In the present study, we assessed cisplatin resistance in seminoma from the perspective of m A, another manner of epigenetic modification. The global m A enrichment of TCam-2 and TCam-2/CDDP was depicted. Then, we elucidated whether transcription factor-activating enhancer-binding protein 2C (TFAP2C) was functionally m A-modified by methyltransferase-like protein 3 (METTL3), which acted as an m A 'writer', and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which acted as an m A 'reader'. Enhanced stability of TFAP2C mRNA promoted seminoma cell survival under cisplatin treatment burden probably through up-regulation of DNA repair-related genes. Hopefully, this study will help improve our understanding of the subtleties of the tumour cellular coping strategy in response to chemotherapy. Targeting factors that are involved in m A methylation may be an effective strategy for circumventing cisplatin resistance in seminoma.