{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:54:38Z","timestamp":1787003678945,"version":"build-2736575974"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T00:00:00Z","timestamp":1739318400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T00:00:00Z","timestamp":1739318400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82160405"],"award-info":[{"award-number":["82160405"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Science and Technology Plan of Jiangxi Province","award":["20213BCJ22013"],"award-info":[{"award-number":["20213BCJ22013"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Zinc finger CCHC-type containing 4 (ZCCHC4) is a newly discovered\n                    <jats:italic>N<\/jats:italic>\n                    <jats:sup>6<\/jats:sup>\n                    -methyladenosine (m\n                    <jats:sup>6<\/jats:sup>\n                    A) RNA methyltransferase (MTase), which possesses an m\n                    <jats:sup>6<\/jats:sup>\n                    A MTase domain and an RNA-binding protein (RBP) Znf domain. Aberrantly expressed ZCCHC4 has been found to be correlated with poor prognosis and chemoresistance in various tumors, such as hepatocellular carcinoma, lung cancer and colorectal cancer. However, the expression and functional analysis of the role of ZCCHC4 in esophageal cancer (ESCA) is still elusive. The expression of ZCCHC4 in esophageal cancer tissues was evaluated by qPT-PCR and western blot. Serum esophageal tumor markers are detected by electrochemiluminescence immunoassay. Relationship between ZCCHC4 expression and pathway enrichment analysis were analyzed by R. The reactive oxygen species (ROS), cell proliferation, cell cycle and apoptosis of ZCCHC4 in esophageal squamous cell carcinoma (ESCC) cells tested by CCK8 assay and flow cytometry assay. Aberrant expression of ZCCHC4 is associated with cancer stages, lymph node metastasis (LNM), and tumor histology,\u00a0and poorer Overall Survival (OS) in esophageal cancer. The mRNA level of ZCCHC4 in esophageal cancer patients correlates with serum carcinoembryonic antigen (CEA) levels, Squamous Cell Carcinoma (SCC) markers, and tissue polypeptide antigen (TPA) levels. Knockdown of ZCCHC4 induces DNA damage, leading to an elevation of reactive oxygen species (ROS), which in turn triggers S-phase arrest, enhances apoptosis, augments sensitivity to cisplatin treatment, and inhibits proliferation in esophageal cancer cells. Conversely, overexpression of ZCCHC4 promotes proliferation, inhibits apoptosis, and increases resistance to cisplatin in esophageal cancer cells. Furthermore, scavenging ROS reverses the effects of ZCCHC4 downregulation on both proliferation and apoptosis in esophageal cancer cells. Additionally, downregulation of ZCCHC4 inhibits the progression of esophageal cancer and reduces cisplatin resistance in vivo. In summary, downregulation of ZCCHC4 leads to increased sensitivity of ESCC cells to cisplatin, inhibits proliferation, and promotes apoptosis in esophageal cancer cells, potentially via the ROS\/c-myc axis. The study suggests a potential adjunctive role for ZCCHC4 in the diagnosis and treatment of esophageal cancer and aids in further understanding the underlying mechanisms in ESCA progression.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-89628-3","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T22:14:57Z","timestamp":1739312097000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["ZCCHC4 regulates esophageal cancer progression and cisplatin resistance through ROS\/c-myc axis"],"prefix":"10.1038","volume":"15","author":[{"given":"Lihua","family":"Yao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangyi","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangmin","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaozhong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,12]]},"reference":[{"key":"89628_CR1","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","volume":"68","author":"F Bray","year":"2018","unstructured":"Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394\u2013424 (2018).","journal-title":"CA Cancer J. Clin."},{"key":"89628_CR2","doi-asserted-by":"publisher","first-page":"15290","DOI":"10.1038\/ncomms15290","volume":"8","author":"J Chang","year":"2017","unstructured":"Chang, J. et al. Genomic analysis of oesophageal squamous-cell carcinoma identifies alcohol drinking-related mutation signature and genomic alterations. Nat. Commun. 8, 15290 (2017).","journal-title":"Nat. Commun."},{"key":"89628_CR3","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1186\/s12876-021-01888-1","volume":"21","author":"MH Hsu","year":"2021","unstructured":"Hsu, M. H. et al. Long-term outcomes of endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma in Taiwan. BMC Gastroenterol. 21, 308 (2021).","journal-title":"BMC Gastroenterol."},{"key":"89628_CR4","doi-asserted-by":"publisher","first-page":"5042","DOI":"10.1038\/s41467-019-12923-x","volume":"10","author":"W Ren","year":"2019","unstructured":"Ren, W. et al. Structure and regulation of ZCCHC4 in m(6)A-methylation of 28S rRNA. Nat. Commun. 10, 5042 (2019).","journal-title":"Nat. Commun."},{"key":"89628_CR5","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1038\/s41576-020-00302-y","volume":"22","author":"F Gebauer","year":"2021","unstructured":"Gebauer, F., Schwarzl, T., Valcarcel, J. & Hentze, M. W. RNA-binding proteins in human genetic disease. Nat. Rev. Genet. 22, 185\u2013198 (2021).","journal-title":"Nat. Rev. Genet."},{"key":"89628_CR6","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1016\/j.semcancer.2022.03.018","volume":"86","author":"S Wang","year":"2022","unstructured":"Wang, S., Sun, Z., Lei, Z. & Zhang, H. T. RNA-binding proteins and cancer metastasis. Semin Cancer Biol. 86, 748\u2013768 (2022).","journal-title":"Semin Cancer Biol."},{"key":"89628_CR7","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1016\/j.semcancer.2022.03.025","volume":"86","author":"W Li","year":"2022","unstructured":"Li, W., Deng, X. & Chen, J. RNA-binding proteins in regulating mRNA stability and translation: roles and mechanisms in cancer. Semin Cancer Biol. 86, 664\u2013677 (2022).","journal-title":"Semin Cancer Biol."},{"key":"89628_CR8","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1038\/s41589-018-0184-3","volume":"15","author":"H Ma","year":"2019","unstructured":"Ma, H. et al. N(6-)Methyladenosine methyltransferase ZCCHC4 mediates ribosomal RNA methylation. Nat. Chem. Biol. 15, 88\u201394 (2019).","journal-title":"Nat. Chem. Biol."},{"key":"89628_CR9","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1038\/s41392-022-01033-8","volume":"7","author":"H Zhu","year":"2022","unstructured":"Zhu, H. et al. RNA-binding protein ZCCHC4 promotes human cancer chemoresistance by disrupting DNA-damage-induced apoptosis. Signal. Transduct. Target. Ther. 7, 240 (2022).","journal-title":"Signal. Transduct. Target. Ther."},{"key":"89628_CR10","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1186\/s13045-021-01173-4","volume":"14","author":"Z Zhang","year":"2021","unstructured":"Zhang, Z. et al. M(6)a regulators as predictive biomarkers for chemotherapy benefit and potential therapeutic targets for overcoming chemotherapy resistance in small-cell lung cancer. J. Hematol. Oncol. 14, 190 (2021).","journal-title":"J. Hematol. Oncol."},{"key":"89628_CR11","doi-asserted-by":"publisher","first-page":"W509","DOI":"10.1093\/nar\/gkaa407","volume":"48","author":"T Li","year":"2020","unstructured":"Li, T. et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 48, W509\u2013W514 (2020).","journal-title":"Nucleic Acids Res."},{"key":"89628_CR12","doi-asserted-by":"publisher","first-page":"730337","DOI":"10.3389\/fcell.2021.730337","volume":"9","author":"L Yao","year":"2021","unstructured":"Yao, L. et al. Investigation on the potential correlation between TP53 and esophageal Cancer. Front. Cell. Dev. Biol. 9, 730337 (2021).","journal-title":"Front. Cell. Dev. Biol."},{"key":"89628_CR13","doi-asserted-by":"crossref","unstructured":"Luo, C. et al. Upregulation of Yin-Yang-1 Associates with Proliferation and Glutamine Metabolism in Esophageal Carcinoma. Int J Genomics (2022) 9305081. (2022).","DOI":"10.1155\/2022\/9305081"},{"key":"89628_CR14","doi-asserted-by":"publisher","first-page":"e249","DOI":"10.1038\/cddis.2011.134","volume":"3","author":"MA Kang","year":"2012","unstructured":"Kang, M. A., So, E. Y., Simons, A. L., Spitz, D. R. & Ouchi, T. DNA damage induces reactive oxygen species generation through the H2AX-Nox1\/Rac1 pathway. Cell. Death Dis. 3, e249 (2012).","journal-title":"Cell. Death Dis."},{"key":"89628_CR15","doi-asserted-by":"publisher","first-page":"102956","DOI":"10.1016\/j.redox.2023.102956","volume":"68","author":"L Meng","year":"2023","unstructured":"Meng, L. et al. MIOX inhibits autophagy to regulate the ROS -driven inhibition of STAT3\/c-Myc-mediated epithelial-mesenchymal transition in clear cell renal cell carcinoma. Redox Biol. 68, 102956 (2023).","journal-title":"Redox Biol."},{"key":"89628_CR16","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1038\/s41575-021-00419-3","volume":"18","author":"AP Thrift","year":"2021","unstructured":"Thrift, A. P. Global burden and epidemiology of Barrett oesophagus and oesophageal cancer. Nat. Rev. Gastroenterol. Hepatol. 18, 432\u2013443 (2021).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"89628_CR17","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1007\/s13402-019-00488-2","volume":"43","author":"A Fatehi Hassanabad","year":"2020","unstructured":"Fatehi Hassanabad, A., Chehade, R., Breadner, D. & Raphael, J. Esophageal carcinoma: towards targeted therapies. Cell. Oncol. (Dordr). 43, 195\u2013209 (2020).","journal-title":"Cell. Oncol. (Dordr)"},{"key":"89628_CR18","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1038\/s41392-020-00323-3","volume":"5","author":"YM Yang","year":"2020","unstructured":"Yang, Y. M., Hong, P., Xu, W. W., He, Q. Y. & Li, B. Advances in targeted therapy for esophageal cancer. Signal. Transduct. Target. Ther. 5, 229 (2020).","journal-title":"Signal. Transduct. Target. Ther."},{"key":"89628_CR19","doi-asserted-by":"crossref","unstructured":"Businello, G. et al. The pathologic and molecular Landscape of esophageal squamous cell carcinogenesis. Cancers (Basel) 12, 2160 (2020).","DOI":"10.3390\/cancers12082160"},{"key":"89628_CR20","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/s13046-024-02965-5","volume":"43","author":"K Chen","year":"2024","unstructured":"Chen, K. et al. The epigenetic downregulation of LncGHRLOS mediated by RNA m6A methylase ZCCHC4 promotes colorectal cancer tumorigenesis. J. Exp. Clin. Cancer Res. 43, 44 (2024).","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"89628_CR21","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1093\/nar\/gkz1147","volume":"48","author":"R Pinto","year":"2020","unstructured":"Pinto, R. et al. The human methyltransferase ZCCHC4 catalyses N6-methyladenosine modification of 28S ribosomal RNA. Nucleic Acids Res. 48, 830\u2013846 (2020).","journal-title":"Nucleic Acids Res."},{"key":"89628_CR22","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.semcdb.2017.05.023","volume":"80","author":"JN Moloney","year":"2018","unstructured":"Moloney, J. N. & Cotter, T. G. ROS signalling in the biology of cancer. Semin Cell. Dev. Biol. 80, 50\u201364 (2018).","journal-title":"Semin Cell. Dev. Biol."},{"key":"89628_CR23","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1038\/s41568-021-00435-0","volume":"22","author":"EC Cheung","year":"2022","unstructured":"Cheung, E. C. & Vousden, K. H. The role of ROS in tumour development and progression. Nat. Rev. Cancer. 22, 280\u2013297 (2022).","journal-title":"Nat. Rev. Cancer"},{"key":"89628_CR24","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1007\/s00204-022-03421-z","volume":"97","author":"HS Tuli","year":"2023","unstructured":"Tuli, H. S. et al. Molecular mechanisms behind ROS regulation in cancer: a balancing act between augmented tumorigenesis and cell apoptosis. Arch. Toxicol. 97, 103\u2013120 (2023).","journal-title":"Arch. Toxicol."},{"key":"89628_CR25","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/s11658-023-00449-6","volume":"28","author":"L Wang","year":"2023","unstructured":"Wang, L. et al. Melatonin and erastin emerge synergistic anti-tumor effects on oral squamous cell carcinoma by inducing apoptosis, ferroptosis, and inhibiting autophagy through promoting ROS. Cell. Mol. Biol. Lett. 28, 36 (2023).","journal-title":"Cell. Mol. Biol. Lett."},{"key":"89628_CR26","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/s41571-021-00549-2","volume":"19","author":"R Dhanasekaran","year":"2022","unstructured":"Dhanasekaran, R. et al. The MYC oncogene - the grand orchestrator of cancer growth and immune evasion. Nat. Rev. Clin. Oncol. 19, 23\u201336 (2022).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"89628_CR27","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1038\/nrc2231","volume":"8","author":"N Meyer","year":"2008","unstructured":"Meyer, N. & Penn, L. Z. Reflecting on 25 years with MYC. Nat. Rev. Cancer. 8, 976\u2013990 (2008).","journal-title":"Nat. Rev. Cancer"},{"key":"89628_CR28","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.semcdb.2015.08.003","volume":"43","author":"AL Hsieh","year":"2015","unstructured":"Hsieh, A. L., Walton, Z. E., Altman, B. J., Stine, Z. E. & Dang, C. V. MYC and metabolism on the path to cancer. Semin Cell. Dev. Biol. 43, 11\u201321 (2015).","journal-title":"Semin Cell. Dev. Biol."},{"key":"89628_CR29","unstructured":"Schaub, F. X. et al. C. Grandori, and N. Cancer Genome Atlas, Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas. Cell Syst 6 282\u2013300 e2. (2018)."},{"key":"89628_CR30","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1016\/j.athoracsur.2018.07.077","volume":"107","author":"J Huang","year":"2019","unstructured":"Huang, J. et al. Prognostic significance of c-MYC amplification in esophageal squamous cell carcinoma. Ann. Thorac. Surg. 107, 436\u2013443 (2019).","journal-title":"Ann. Thorac. Surg."},{"key":"89628_CR31","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s12885-022-10464-z","volume":"23","author":"Z Roohinejad","year":"2023","unstructured":"Roohinejad, Z. et al. Upregulation of the c-MYC oncogene and adjacent long noncoding RNAs PVT1 and CCAT1 in esophageal squamous cell carcinoma. BMC Cancer. 23, 34 (2023).","journal-title":"BMC Cancer"},{"key":"89628_CR32","doi-asserted-by":"publisher","first-page":"4473","DOI":"10.1002\/ptr.7913","volume":"37","author":"JI Koo","year":"2023","unstructured":"Koo, J. I. et al. Apoptotic and anti-warburg effect of Morusin via ROS mediated inhibition of FOXM1\/c-Myc signaling in prostate cancer cells. Phytother Res. 37, 4473\u20134487 (2023).","journal-title":"Phytother Res."},{"key":"89628_CR33","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1038\/s41419-018-0498-9","volume":"9","author":"G Wu","year":"2018","unstructured":"Wu, G. et al. c-MYC and reactive oxygen species play roles in tetrandrine-induced leukemia differentiation. Cell. Death Dis. 9, 473 (2018).","journal-title":"Cell. Death Dis."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-89628-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-89628-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-89628-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T10:10:19Z","timestamp":1739355019000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-89628-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,12]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["89628"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-89628-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,12]]},"assertion":[{"value":"21 September 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 February 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 February 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This study was approved by the Medical Ethics Committee of the Second Affiliated Hospital of Nanchang University. Each participant provided a written informed consent for participation.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}}],"article-number":"5149"}}