{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T22:42:52Z","timestamp":1761000172228,"version":"build-2065373602"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Proto-oncogenes are abnormally activated in nearly all types of tumors. However, the epigenetic mechanism of proto-oncogene activation has not yet been well elucidated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The present study involved the construction of a double-stranded cDNA library derived from gastrointestinal cancer cells, followed by high-throughput genome sequencing to select the c-MYC gene associated with colorectal cancer. Through RACE analysis, we identified the antisense RNA MYC-AS1 and its complete sequence. By investigating the cellular functions, expression of MYC-AS1, elucidating its interaction mechanism with the c-MYC gene, and exploring the impact of DNA methylation on MYC-AS1 expression, we uncover the fundamental principles and regulatory mechanisms underlying colorectal cancer development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Here, we show that a subset of proto-oncogenes,including c-MYC, possess antisense RNAs. Upregulation of c-MYC in cancer tissues was attributed to the silencing of its antisense RNA MYC-AS1 via DNA hypermethylation. MYC-AS1 RNA markedly inhibited the proliferation of cancer cells in vitro and impeded tumor growth in nude mice in vivo by repressing the expression of c-MYC via an RNAi mechanism. MYC-AS1 RNA bound directly to the HuR protein in the cytoplasm, enhancing the RNA stability of MYC-AS1. Furthermore, MYC-AS1 inhibited c-MYC-targeted gene LDHA expression. Unlike the well-characterized oncogenic long noncoding RNA PVT1, which is coamplified with MYC and enhances its stability, MYC-AS1 is epigenetically silenced and functions as a tumor suppressor through an RNAi mechanism, revealing a distinct layer of MYC regulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our work provides a novel mechanism by which c-MYC is activated in cancer cells by epigenetic silencing of its antisense RNA, which functions as a tumor suppressor.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fgene.2025.1552009","type":"journal-article","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T22:10:23Z","timestamp":1760998223000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A novel mechanism by which c-MYC is aberrantly activated by epigenetic silencing of its antisense lncRNA in colon cancer"],"prefix":"10.3389","volume":"16","author":[{"given":"Xuming","family":"Hu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ye","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meiying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunfeng","family":"Dou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liping","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gul","family":"Zaib","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huixian","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wang","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shihao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingzhou","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hengmi","family":"Cui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1038\/321702a0","article-title":"A block to elongation is largely responsible for decreased transcription of c-myc in differentiated HL60 cells","volume":"321","author":"Bentley","year":"1986","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1038\/5047","article-title":"Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer","volume":"21","author":"Cameron","year":"1999","journal-title":"Nat. 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