{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T23:56:23Z","timestamp":1768521383617,"version":"3.49.0"},"posted":{"date-parts":[[2025,3,25]]},"group-title":"Cancer Biology","reference-count":53,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T00:00:00Z","timestamp":1742860800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,25]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  Recent studies have demonstrated that a subset of long \u201cnoncoding\u201d RNAs (lncRNAs) produce functional polypeptides and proteins. In this study, we discovered a 132 amino acid protein in human breast cancer cells named XCP (\n                  <jats:underline>X<\/jats:underline>\n                  -linked\n                  <jats:underline>C<\/jats:underline>\n                  ancer-associated\n                  <jats:underline>P<\/jats:underline>\n                  olypeptide), which is encoded by\n                  <jats:italic>lncRNA1456<\/jats:italic>\n                  (a.k.a.\n                  <jats:italic>RHOXF1P3<\/jats:italic>\n                  ), a transcript previously thought to be noncoding.\n                  <jats:italic>lncRNA1456<\/jats:italic>\n                  is a pancreas\u2013 and testis-specific RNA whose gene is located on chromosome X. We found that the expression of\n                  <jats:italic>lncRNA1456<\/jats:italic>\n                  and XCP are highly upregulated in the luminal A, luminal B, and HER2 molecular subtypes of breast cancer. XCP modulates both estrogen-dependent and estrogen-independent growth of breast cancer cells by regulating cancer pathways, as shown in cell and xenograft models. XCP shares some homology with homeodomain-containing proteins and interacts with the histone demethylase plant homeodomain finger protein 8 (PHF8), which is also encoded by an X-linked gene. Mechanistically, XCP stimulates the histone demethylase activity of PHF8 to regulate gene expression in breast cancer cells. These findings identify XCP as a coregulator of transcription and emphasize the need to interrogate the potential functional roles of open reading frames originating from noncoding RNAs.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Statement of Significange<\/jats:title>\n                  <jats:p>XCP, a polypeptide encoded by an X-linked lncRNA, regulates gene expression in breast cancer cells. XCP is a chromatin-associated protein that interacts with the histone demethylase PHF8 and modulates its demethylase activity to regulate gene expression. XCP drives cancer-specific phenotypes and serves as a potential biomarker and\/or target for therapeutic intervention.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.03.21.644649","type":"posted-content","created":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T17:05:33Z","timestamp":1742922333000},"source":"Crossref","is-referenced-by-count":0,"title":["X-Linked Cancer-Associated Polypeptide (XCP) from\n                  <i>lncRNA1456<\/i>\n                  Cooperates with PHF8 to Regulate Gene Expression and Cellular Pathways in Breast Cancer"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0030-5472","authenticated-orcid":false,"given":"Shrikanth S.","family":"Gadad","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1723-579X","authenticated-orcid":false,"given":"Cristel V.","family":"Camacho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuan","family":"Gong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Micah","family":"Thornton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Venkat S.","family":"Malladi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anusha","family":"Nagari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aishwarya","family":"Sundaresan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tulip","family":"Nandu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sneh","family":"Koul","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8786-2986","authenticated-orcid":false,"given":"W. Lee","family":"Kraus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025032800501277000_2025.03.21.644649v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11233"},{"key":"2025032800501277000_2025.03.21.644649v1.2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr209"},{"key":"2025032800501277000_2025.03.21.644649v1.3","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.201800715"},{"key":"2025032800501277000_2025.03.21.644649v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3981"},{"key":"2025032800501277000_2025.03.21.644649v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36826-0"},{"key":"2025032800501277000_2025.03.21.644649v1.6","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-020-1147-3"},{"key":"2025032800501277000_2025.03.21.644649v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2023.121434"},{"key":"2025032800501277000_2025.03.21.644649v1.8","doi-asserted-by":"crossref","unstructured":"Zheng C , Wei Y , Zhang P , Xu L , Zhang Z , Lin K , Hou J , Lv X , et al. (2023) CRISPR\/Cas9 screen uncovers functional translation of cryptic lncRNA-encoded open reading frames in human cancer. J Clin Invest 133","DOI":"10.1172\/JCI159940"},{"key":"2025032800501277000_2025.03.21.644649v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2023.01.023"},{"key":"2025032800501277000_2025.03.21.644649v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/nature21034"},{"key":"2025032800501277000_2025.03.21.644649v1.11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1809105116"},{"key":"2025032800501277000_2025.03.21.644649v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0794-7"},{"key":"2025032800501277000_2025.03.21.644649v1.13","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz646"},{"key":"2025032800501277000_2025.03.21.644649v1.14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0287133"},{"key":"2025032800501277000_2025.03.21.644649v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-023-05092-7"},{"key":"2025032800501277000_2025.03.21.644649v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcp.2023.101913"},{"key":"2025032800501277000_2025.03.21.644649v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2023.10.040"},{"key":"2025032800501277000_2025.03.21.644649v1.18","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-22-0123"},{"key":"2025032800501277000_2025.03.21.644649v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2015.06.023"},{"key":"2025032800501277000_2025.03.21.644649v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.03.002"},{"key":"2025032800501277000_2025.03.21.644649v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2010.8"},{"key":"2025032800501277000_2025.03.21.644649v1.22","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp480"},{"key":"2025032800501277000_2025.03.21.644649v1.23","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2010.110"},{"key":"2025032800501277000_2025.03.21.644649v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2010.75"},{"key":"2025032800501277000_2025.03.21.644649v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2016.03.010"},{"key":"2025032800501277000_2025.03.21.644649v1.26","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgu099"},{"key":"2025032800501277000_2025.03.21.644649v1.27","doi-asserted-by":"publisher","DOI":"10.1002\/bies.201400103"},{"key":"2025032800501277000_2025.03.21.644649v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2024.10.012"},{"key":"2025032800501277000_2025.03.21.644649v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2024.12.010"},{"key":"2025032800501277000_2025.03.21.644649v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108815"},{"key":"2025032800501277000_2025.03.21.644649v1.31","doi-asserted-by":"publisher","DOI":"10.1080\/15476286.2023.2279845"},{"key":"2025032800501277000_2025.03.21.644649v1.32","doi-asserted-by":"publisher","DOI":"10.1101\/gr.6049"},{"key":"2025032800501277000_2025.03.21.644649v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.62"},{"key":"2025032800501277000_2025.03.21.644649v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2008.01.011"},{"key":"2025032800501277000_2025.03.21.644649v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2011.04.021"},{"key":"2025032800501277000_2025.03.21.644649v1.36","doi-asserted-by":"publisher","DOI":"10.1101\/pdb.prot5652"},{"key":"2025032800501277000_2025.03.21.644649v1.37","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku1060"},{"key":"2025032800501277000_2025.03.21.644649v1.38","doi-asserted-by":"publisher","DOI":"10.1002\/0471250953.bi1112s47"},{"key":"2025032800501277000_2025.03.21.644649v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-9525(00)02024-2"},{"key":"2025032800501277000_2025.03.21.644649v1.40","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkh131"},{"key":"2025032800501277000_2025.03.21.644649v1.41","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-3167-5_2"},{"key":"2025032800501277000_2025.03.21.644649v1.42","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.7b00670"},{"key":"2025032800501277000_2025.03.21.644649v1.43","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3838"},{"key":"2025032800501277000_2025.03.21.644649v1.44","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku1071"},{"key":"2025032800501277000_2025.03.21.644649v1.45","doi-asserted-by":"crossref","unstructured":"Sievers F , Wilm A , Dineen D , Gibson TJ , Karplus K , Li W , Lopez R , McWilliam H , et al. (2011) Fast, scalable generation of high quality protein multiple sequence alignments using Clustal Omega. Molecular Systems Biology 7","DOI":"10.1038\/msb.2011.75"},{"key":"2025032800501277000_2025.03.21.644649v1.46","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2013-14-4-r36"},{"key":"2025032800501277000_2025.03.21.644649v1.47","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1630"},{"key":"2025032800501277000_2025.03.21.644649v1.48","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2009-10-3-r25"},{"key":"2025032800501277000_2025.03.21.644649v1.49","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp352"},{"key":"2025032800501277000_2025.03.21.644649v1.50","doi-asserted-by":"publisher","DOI":"10.1101\/gr.136184.111"},{"key":"2025032800501277000_2025.03.21.644649v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2012.101"},{"key":"2025032800501277000_2025.03.21.644649v1.52","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw257"},{"key":"2025032800501277000_2025.03.21.644649v1.53","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-2891-1_11"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.03.21.644649","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T08:20:59Z","timestamp":1768465259000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.03.21.644649"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,25]]},"references-count":53,"URL":"https:\/\/doi.org\/10.1101\/2025.03.21.644649","relation":{},"subject":[],"published":{"date-parts":[[2025,3,25]]},"subtype":"preprint"}}