c-Myc inactivation of p53 through the pan-cancer lncRNA MILIP drives cancer pathogenesis

• Published in: Nature communications Vol. 11; no. 1; pp. 4980 - 12
• Main Authors: Feng, Yu Chen, Liu, Xiao Ying, Teng, Liu, Ji, Qiang, Wu, Yongyan, Li, Jin Ming, Gao, Wei, Zhang, Yuan Yuan, La, Ting, Tabatabaee, Hessam, Yan, Xu Guang, Jamaluddin, M. Fairuz B., Zhang, Didi, Guo, Su Tang, Scott, Rodney J., Liu, Tao, Thorne, Rick F., Zhang, Xu Dong, Jin, Lei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.10.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/105; 13/106; 13/109; 13/2; 13/31; 13/89; 14/19; 14/32; 38/15; 38/70; 38/91; 45/71; 45/77; 631/337/384/2568; 631/67/1347; 631/67/1612; 631/67/395; 96/1; c-Myc protein; Cancer; Cell proliferation; Cell survival; Deactivation; Homeostasis; Homology; Humanities and Social Sciences; Inactivation; MDM2 protein; miRNA; multidisciplinary; Myc protein; Negative feedback; p53 Protein; Pathogenesis; Ribonucleic acid; RNA; Science; Science (multidisciplinary); SUMO protein; Survival; Transcription; Tumor suppressor genes; Tumorigenicity; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-18735-8

The functions of the proto-oncoprotein c-Myc and the tumor suppressor p53 in controlling cell survival and proliferation are inextricably linked as “Yin and Yang” partners in normal cells to maintain tissue homeostasis: c-Myc induces the expression of ARF tumor suppressor (p14 ARF in human and p19 ARF in mouse) that binds to and inhibits mouse double minute 2 homolog (MDM2) leading to p53 activation, whereas p53 suppresses c-Myc through a combination of mechanisms involving transcriptional inactivation and microRNA-mediated repression. Nonetheless, the regulatory interactions between c-Myc and p53 are not retained by cancer cells as is evident from the often-imbalanced expression of c-Myc over wildtype p53. Although p53 repression in cancer cells is frequently associated with the loss of ARF, we disclose here an alternate mechanism whereby c-Myc inactivates p53 through the actions of the c-Myc-Inducible Long noncoding RNA Inactivating P53 (MILIP). MILIP functions to promote p53 polyubiquitination and turnover by reducing p53 SUMOylation through suppressing tripartite-motif family-like 2 (TRIML2). MILIP upregulation is observed amongst diverse cancer types and is shown to support cell survival, division and tumourigenicity. Thus our results uncover an inhibitory axis targeting p53 through a pan-cancer expressed RNA accomplice that links c-Myc to suppression of p53. c-Myc and p53 operate in a negative feedback manner to maintain cellular homeostasis. Here, the authors report a long noncoding RNA, MILIP as a downstream target of c-Myc and that MILIP represses p53 to support tumorigenicity.