{"doi":"10.1101/2022.08.05.502726","title":"MAPK13 stabilization via m <sup>6</sup> A modification limits anti-cancer efficacy of rapamycin","abstract":"Abstract N 6 -adenosine methylation (m 6 A) is the most abundant mRNA modification that controls gene expression through diverse mechanisms. m 6 A-dependent regulation of oncogenes and tumor suppressors indeed contribute to tumor development. However, the role of m 6 A-mediated gene regulation after drug treatment or resistance is poorly understood. Here, we report that m 6 A modification of mitogen-activated protein kinase 13 ( MAPK13 ) determines the sensitivity of cancer cells to the mechanistic target of rapamycin complex 1 (mTORC1)- targeting chemotherapeutic agent rapamycin. mTORC1 induces m 6 A modification of MAPK13 mRNA at its 3’ untranslated region (3’UTR) through methyltransferase-like 3 (METTL3)-METTL14-Wilms’ tumor 1-associating protein (WTAP) methyltransferase complex, thereby stimulating its mRNA degradation via an m 6 A reader protein YTH domain family protein 2 (YTHDF2). Rapamycin blunts this process and stabilizes MAPK13 . Unexpectedly, MAPK13 silencing suppresses cell growth and enhances rapamycin’s anti-cancer effects, suggesting that MAPK13 is an oncogenic gene activated by rapamycin via a feedback regulation. Together, our data indicate that rapamycin-mediated MAPK13 mRNA stabilization may confer drug resistance, and it can thus be a therapeutic target to sensitize cancer cells to rapamycin.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":310482,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9586,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":293747,"name":"Yujin Chun","orcid":null,"position":1,"is_corresponding":false},{"id":1005721,"name":"Cuauhtemoc B. Ramirez","orcid":"0000-0001-7182-1859","position":2,"is_corresponding":false},{"id":1005722,"name":"Lauren Hoffner","orcid":"0000-0002-2861-9898","position":3,"is_corresponding":false},{"id":633185,"name":"Sunhee Jung","orcid":"0000-0001-5396-4813","position":4,"is_corresponding":false},{"id":1006427,"name":"Ki-Hong Jang","orcid":null,"position":5,"is_corresponding":false},{"id":1005723,"name":"Varvara I. Rubtsova","orcid":"0000-0003-3912-4820","position":6,"is_corresponding":false},{"id":225539,"name":"Cholsoon Jang","orcid":"0000-0001-6651-4213","position":7,"is_corresponding":false},{"id":271342,"name":"Gina Lee","orcid":"0000-0002-8120-9169","position":8,"is_corresponding":false},{"id":1005720,"name":"Joo‐Hwan Kim","orcid":"0000-0002-2999-4411","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":null,"created_at":"2026-07-19T00:33:19.712967Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}