Journal Article Ppublish
PubMed: 41665012 DOI: 10.1093/nar/gkag101
Scaffolding of the H4K5ac chromatin remodeling complex by lncRNA MAHAC mediates epithelial-mesenchymal transition.
Nucleic Acids Res 54(4)
Authors: Kai-Wen Hsu, Jeng-Shou Chang, Joseph Chieh-Yu Lai, Li-Hao Yang, Pei-Hua Peng, Tzu-Chin Lin, Kou-Juey Wu
Affiliations
- Institute of Translational Medicine and New Drug Development, China Medical University, Taichung 404, Taiwan.
- Cancer Genome Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan.
- Division of Neurosurgery, Dept. of Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan.
Abstract
Anchoring of a chromatin remodeler complex by long non-coding RNAs (lncRNAs) is a frequently utilized mechanism for lncRNAs to regulate gene expression. Hypoxia is a microenvironmental condition that plays a crucial role in promoting tumor progression. We previously identified a hypoxia-inducible lncRNA, RP11-390F4.3, that regulates epithelial-mesenchymal transition (EMT) without a delineated mechanism. Here, we show that the lncRNA RP11-390F4.3 (renamed MAHAC: MAintenance of Histone ACetylation) specifically induces histone H4 lysine 5 acetylation (H4K5ac) mark and promotes the deposition of H4K5ac mark on the promoters of EMT transcription factors. MAHAC scaffolds the ILF3/NF90-ILF2-CBP complex, which is co-localized with the members of the complex inside the nucleus under hypoxia. The minimal MAHAC region (nt 686-741) required for scaffolding the complex was mapped, and it induces allosteric activation of H4K5ac in in vitro histone acetyltransferase assay. This minimal MAHAC region is essential for hypoxia-induced EMT, migration, invasion, and H4K5ac activation. These findings demonstrate that hypoxia-induced MAHAC represents an unexplored allosteric regulator of H4K5ac that activates EMT and induces tumor progression.
MeSH
Epithelial-Mesenchymal Transition, Neoplasms, Chromatin, Histones, Nucleic Acids, Hypoxia, Rna, Long Noncoding