{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"American Association for Cancer Research"}],"indexed":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T18:37:14Z","timestamp":1770057434750,"version":"3.49.0"},"posted":{"date-parts":[[2026,2,2]]},"reference-count":0,"publisher":"American Association for Cancer Research (AACR)","license":[{"start":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:00:00Z","timestamp":1769990400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<div>Abstract<p>Aggressive metastatic cancer remains a major clinical challenge because of the unclear underlying mechanisms and the limited treatment options available. N<sup>6<\/sup>-Methyladenosine (m<sup>6<\/sup>A) is a reversible modification of RNA that is frequently altered in cancer, and inhibitors targeting regulators of this process have been shown to block tumorigenesis. A better understanding of the role of m<sup>6<\/sup>A modifications in driving metastatic properties could help reveal potential strategies to prevent and treat metastasis. In this study, we discovered loss of the m<sup>6<\/sup>A writer complex component ZC3H13 as a key regulator of metastatic progression. Co-loss of <i>ZC3H13<\/i> together with <i>RB1<\/i> and <i>BRCA2<\/i> occurred in patients with metastatic prostate cancer. Functional <i>in vitro<\/i> and <i>in vivo<\/i> assays demonstrated that <i>ZC3H13<\/i> loss changes m<sup>6<\/sup>A writer complex activity and target specificity, leading to decreased m<sup>6<\/sup>A methylation and increased stability of transcripts that promote migration and invasion. Treatment with FDA-approved m<sup>6<\/sup>A demethylase inhibitors effectively reduced the metastatic capabilities of ZC3H13-deficient cells. Together, these findings provide insights into how the m<sup>6<\/sup>A writer complex selectively methylates mRNAs, highlight the pathologic consequences of altered writer complex composition in cancer, and reveal therapeutic avenues for patients with metastatic cancer.<\/p>Significance:<p>FDA-approved m<sup>6<\/sup>A demethylase inhibitors can inhibit metastasis driven by ZC3H13 deficiency, which reduces m<sup>6<\/sup>A methylation of select transcripts involved in migration and invasion, providing potential therapeutic options for patients with metastatic cancer.<\/p><\/div><\/jats:p>","DOI":"10.1158\/0008-5472.c.8284908","type":"posted-content","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T08:20:36Z","timestamp":1770020436000},"source":"Crossref","is-referenced-by-count":0,"title":["Data from <i>ZC3H13<\/i> Loss Drives Cancer Metastatic Progression by Disrupting m<sup>6<\/sup>A RNA Methylation"],"prefix":"10.1158","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3992-5786","authenticated-orcid":false,"given":"\u00d3scar","family":"Monteagudo-Garc\u00eda","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2730-3397","authenticated-orcid":false,"given":"Paz","family":"Nombela","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5868-6768","authenticated-orcid":false,"given":"\u00c1ngel Carlos","family":"Rom\u00e1n","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1138-4492","authenticated-orcid":false,"given":"Vicente","family":"Fern\u00e1ndez-Rodero","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3058-5631","authenticated-orcid":false,"given":"Berta","family":"Casar","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9659-4613","authenticated-orcid":false,"given":"Devi Prasad","family":"Bhattarai","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1015-9923","authenticated-orcid":false,"given":"Diego","family":"Alonso-L\u00f3pez","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5689-5073","authenticated-orcid":false,"given":"Diana","family":"Loa-Mes\u00f3n","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6746-6807","authenticated-orcid":false,"given":"Daniela","family":"Barros-Silva","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3171-4666","authenticated-orcid":false,"given":"Rui","family":"Henrique","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4186-5345","authenticated-orcid":false,"given":"Carmen","family":"Jer\u00f3nimo","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8658-2552","authenticated-orcid":false,"given":"Guido W.","family":"Jenster","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5363-2525","authenticated-orcid":false,"given":"Elena S.","family":"Martens-Uzunova","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2374-2045","authenticated-orcid":false,"given":"Francesca","family":"Aguilo","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7352-9392","authenticated-orcid":false,"given":"Sandra","family":"Blanco","sequence":"first","affiliation":[]}],"member":"1086","container-title":[],"original-title":[],"deposited":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T08:20:36Z","timestamp":1770020436000},"score":1,"resource":{"primary":{"URL":"https:\/\/aacr.figshare.com\/collections\/Data_from_i_ZC3H13_i_Loss_Drives_Cancer_Metastatic_Progression_by_Disrupting_m_sup_6_sup_A_RNA_Methylation\/8284908"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,2]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1158\/0008-5472.c.8284908","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1158\/0008-5472.CAN-24-3975","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2026,2,2]]},"subtype":"other"}}