{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:53:44Z","timestamp":1791298424111,"version":"4.1.0"},"reference-count":33,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Carcinogenesis"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>EIF2AK2, also known as PKR, is a stress\u2010responsive kinase that regulates multiple cellular processes, including autophagy, apoptosis, and tumor progression. However, the mechanisms underlying EIF2AK2 stability and function in bladder cancer (BLCA) remain underexplored. In this study, we investigated the mechanisms governing post\u2010translational EIF2AK2 expression and its impact on BLCA progression. Through a luciferase\u2010based screening of candidate E3 ubiquitin ligases, we identified CNOT4 as a potential regulator of EIF2AK2. Bioinformatics analysis of public BLCA transcriptomic datasets showed that CNOT4 expression is significantly decreased in BLCA tissues relative to that in normal bladder tissues, and reduced CNOT4 levels are associated with unfavorable clinical outcomes. Functional assays demonstrated that CNOT4 overexpression suppresses viability and motility, while promoting apoptosis in BLCA cells. Moreover, CNOT4 inhibited autophagy and related signaling pathways. Mechanistic analyses revealed that CNOT4 interacted with EIF2AK2 and promoted its K48\u2010linked ubiquitination and proteasomal degradation. Restoration of EIF2AK2 expression largely reversed the tumor\u2010suppressive effects of CNOT4, indicating that EIF2AK2 acts as a key downstream effector. Consistent with these findings, CNOT4 overexpression significantly suppressed tumor growth in a BLCA xenograft model. Collectively, our observations identify CNOT4 as a previously unrecognized EIF2AK2 stability regulator and reveal that CNOT4 suppresses BLCA progression by promoting EIF2AK2 degradation and thereby suppressing autophagy. These results reveal a novel mechanism for the post\u2010translational modulation of EIF2AK2 and suggest a potential therapeutic target for BLCA.<\/jats:p>","DOI":"10.1002\/mc.70187","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:33:36Z","timestamp":1791297216000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CNOT4 Suppresses Bladder Cancer Progression by Promoting Ubiquitination\u2010Mediated Degradation of EIF2AK2 and Inhibiting Autophagy"],"prefix":"10.1002","author":[{"given":"Zechun","family":"Peng","sequence":"first","affiliation":[{"name":"Department of Urology, Nanjing First Hospital Nanjing Medical University Nanjing Jiangsu Province China"},{"name":"Department of Urology II The Second Affiliated Hospital of Hainan Medical University Haikou Hainan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5532-5641","authenticated-orcid":false,"given":"Ruipeng","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Urology, Nanjing First Hospital Nanjing Medical University Nanjing Jiangsu Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0844-9032","authenticated-orcid":false,"given":"Tiemin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery The Second Affiliated Hospital of Hainan Medical University Haikou Hainan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Urology II The Second Affiliated Hospital of Hainan Medical University Haikou Hainan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","DOI":"10.7189\/jogh.13.04109","article-title":"The Global Landscape of Bladder Cancer Incidence and Mortality in 2020 and Projections to 2040","volume":"13","author":"Zhang Y.","year":"2023","journal-title":"Journal of Global Health"},{"issue":"3","key":"e_1_2_10_3_1","first-page":"229","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray F.","year":"2024","journal-title":"CA: A Cancer Journal for Clinicians"},{"issue":"5","key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/j.eururo.2025.02.019","article-title":"European Association of Urology Guidelines on Muscle\u2010Invasive and Metastatic Bladder Cancer: Summary of the 2025 Guidelines","volume":"87","author":"Heijden A. G.","year":"2025","journal-title":"European Urology"},{"issue":"1","key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1007\/s00345-025-05960-3","article-title":"Management of Clinical Stage T3\/T4 Bladder Cancer: A Review","volume":"43","author":"Escobar D.","year":"2025","journal-title":"World Journal of Urology"},{"issue":"7","key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.3390\/cancers17071105","article-title":"Patients With Metastatic or Locally Advanced Bladder Cancer Not Undergoing Systemic Oncological Treatment\u2010Characteristics and Long\u2010Term Outcome in a Single\u2010Center Danish Cohort","volume":"17","author":"Thorsteinsson K.","year":"2025","journal-title":"Cancers"},{"issue":"1","key":"e_1_2_10_7_1","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1186\/s12943-024-02046-3","article-title":"Ubiquitination and Deubiquitination in Cancer: From Mechanisms to Novel Therapeutic Approaches","volume":"23","author":"Liu F.","year":"2024","journal-title":"Molecular Cancer"},{"key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-3-030-38266-7_1","article-title":"Ubiquitin\u2010Regulated Cell Proliferation and Cancer","volume":"1233","author":"P\u00e9rez\u2010Benavente B.","year":"2020","journal-title":"Advances in Experimental Medicine and Biology"},{"issue":"3","key":"e_1_2_10_9_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.jbc.2021.101077","article-title":"Deubiquitinating Enzymes (DUBs): Regulation, Homeostasis, and Oxidative Stress Response","volume":"297","author":"Snyder N. A.","year":"2021","journal-title":"Journal of Biological Chemistry"},{"issue":"21","key":"e_1_2_10_10_1","doi-asserted-by":"crossref","first-page":"6682","DOI":"10.3390\/molecules26216682","article-title":"Structural Diversity of Ubiquitin E3 Ligase","volume":"26","author":"Toma\u2010Fukai S.","year":"2021","journal-title":"Molecules"},{"key":"e_1_2_10_11_1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2023.1226057","article-title":"E3 Ubiquitin Ligases and Deubiquitinases in Bladder Cancer Tumorigenesis and Implications for Immunotherapies","volume":"14","author":"Wang M.","year":"2023","journal-title":"Frontiers in Immunology"},{"issue":"20","key":"e_1_2_10_12_1","doi-asserted-by":"crossref","DOI":"10.1002\/advs.202408311","article-title":"RNF112 Facilitates Ubiquitin\u2010Mediated Degradation of c\u2010Myc, Suppressing Proliferation, Migration and Lipid Synthesis in Bladder Cancer","volume":"12","author":"Xiong K.","year":"2025","journal-title":"Advanced Science"},{"issue":"10","key":"e_1_2_10_13_1","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1158\/1541-7786.MCR-20-1029","article-title":"TRAF4 Inhibits Bladder Cancer Progression by Promoting BMP\/SMAD Signaling","volume":"20","author":"Iyengar P. 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