ORIGINAL RESEARCH article
Front. Genet.
Sec. Cancer Genetics and Oncogenomics
Volume 16 - 2025 | doi: 10.3389/fgene.2025.1552009
This article is part of the Research TopicComparative Genomics and Functional Genomics Analyses in CancerView all 9 articles
A novel mechanism by which c-MYC is aberrantly activated by epigenetic silencing of its antisense lncRNA in colon cancer
Provisionally accepted- 1Institute of Epigenetics and Epigenomics, College of Animal Science and technology, Yangzhou University, Yangzhou, Jiangsu Province, China
- 2College of Medicine, Yangzhou University,, Yangzhou, China
- 3Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, Beijing Municipality, China
- 4Department of General Surgery, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
- 5Foothills Medical Centre, Alberta Health Services, Calgary, Canada
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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. 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 co-amplified 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. 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. Statement of significance: The present study reveals a novel mechanism of tumorigenesis by which oncogenes are activated by epigenetic silencing of their counterpart antisense lncRNAs. Identifying MYC-AS1 as a tumor suppressor may facilitate the design of new anticancer drugs.
Keywords: antisense RNA, c-Myc, DNA Methylation, Cancer, HuR
Received: 27 Dec 2024; Accepted: 03 Oct 2025.
Copyright: © 2025 Hu, Wei, Zhang, Dou, Wang, Zaib, Wu, Guo, Wang, Chen, Xu, Xiang, Guo and Cui. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Mingzhou Guo, mzguo@hotmail.com
Hengmi Cui, hmcui@yzu.edu.cn
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