NSD3S stabilizes MYC through hindering its interaction with FBXW7

• Type of Material: Article
• Authors: Valentina Gonzalez-Pecchi, Emory University; Albert K. Kwan, Emory University; Sean Doyle, Emory University; Andrey Ivanov, Emory University; Yuhong Du, Emory University; Haian Fu, Emory University
• Language: English
• Date: 2020-06-01
• Publisher: Oxford University Press
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) (2019). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1093/jmcb/mjz098
• Title of Journal or Parent Work: Journal of Molecular Cell Biology
• Volume: 12
• Issue: 6
• Start Page: 438
• End Page: 447
• Grant/Funding Information: V.G.-P. was supported by Fulbright Scholarship and Becas Chile-CONICYT for her graduate studies.; This research was supported in part by the National Institute of Health NCI Cancer Target Discovery and Development (CTD2) Network grants (U01CA168449 and U01CA217875), Georgia Cancer Coalition Award from Georgia Research Alliance (H.F.), the Emory Chemical Biology Discovery Center, and Winship Cancer Institute (NIH 5P30CA138292).
• Keywords: Protein-protein interaction; C-MYC; Cell Biology; Domain; MYC; cancer; Expression; Nut midlife carcinoma; FBXW7; Max; DNA-Binding; Oncoprotein; Life Sciences & Biomedicine; NSD3S; Transformation; Science & Technology; Phosphorylation; protein-protein interaction
• Research Categories: Biology, Cell; Health Sciences, Pharmacology; Biology, Genetics; Health Sciences, Oncology

Abstract

The MYC transcription factor plays a key role in cell growth control. Enhanced MYC protein stability has been found to promote tumorigenesis. Thus, understanding how MYC stability is controlled may have significant implications for revealing MYC-driven growth regulatory mechanisms in physiological and pathological processes. Our previous work identified the histone lysine methyltransferase nuclear receptor binding SET domain protein 3 (NSD3) as a MYC modulator. NSD3S, a noncatalytic isoform of NSD3 with oncogenic activity, appears to bind, stabilize, and activate the transcriptional activity of MYC. However, the mechanism by which NSD3S stabilizes MYC remains to be elucidated. To uncover the nature of the interaction and the underlying mechanism of MYC regulation by NSD3S, we characterized the binding interface between both proteins by narrowing the interface to a 15-amino acid region in NSD3S that is partially required for MYC regulation. Mechanistically, NSD3S binds to MYC and reduces the association of F-box and WD repeat domain containing 7 (FBXW7) with MYC, which results in suppression of FBXW7-mediated proteasomal degradation of MYC and an increase in MYC protein half-life. These results support a critical role for NSD3S in the regulation of MYC function and provide a novel mechanism for NSD3S oncogenic function through inhibition of FBXW7-mediated degradation of MYC.