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

Yu Chen Feng, Xiao Ying Liu, Liu Teng, Qiang Ji, Yongyan Wu, Jin Ming Li, Wei Gao, Yuan Yuan Zhang, Ting La, Hessam Tabatabaee, Xu Guang Yan, M. Fairuz B. Jamaluddin, Didi Zhang, Su Tang Guo, Rodney J. Scott, Tao Liu, Rick F. Thorne, Xu Dong Zhang () and Lei Jin ()
Additional contact information
Yu Chen Feng: The University of Newcastle
Xiao Ying Liu: Henan Provincial People’s Hospital and People’s Hospital of Zhengzhou University, Academy of Medical Science, Zhengzhou University, Zhengzhou
Liu Teng: Henan Provincial People’s Hospital and People’s Hospital of Zhengzhou University, Academy of Medical Science, Zhengzhou University, Zhengzhou
Qiang Ji: Henan Provincial People’s Hospital and People’s Hospital of Zhengzhou University, Academy of Medical Science, Zhengzhou University, Zhengzhou
Yongyan Wu: Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, the first affiliated hospital, Shanxi Medical University
Jin Ming Li: Henan Provincial People’s Hospital and People’s Hospital of Zhengzhou University, Academy of Medical Science, Zhengzhou University, Zhengzhou
Wei Gao: Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, the first affiliated hospital, Shanxi Medical University
Yuan Yuan Zhang: The University of Newcastle
Ting La: The University of Newcastle
Hessam Tabatabaee: The University of Newcastle
Xu Guang Yan: The University of Newcastle
M. Fairuz B. Jamaluddin: The University of Newcastle
Didi Zhang: John Hunter Hospital, Hunter New England Health
Su Tang Guo: Shanxi Cancer Hospital and Institute, Taiyuan
Rodney J. Scott: The University of Newcastle
Tao Liu: University of New South Wales
Rick F. Thorne: The University of Newcastle
Xu Dong Zhang: The University of Newcastle
Lei Jin: Henan Provincial People’s Hospital and People’s Hospital of Zhengzhou University, Academy of Medical Science, Zhengzhou University, Zhengzhou

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract 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 (p14ARF in human and p19ARF 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.

Date: 2020
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DOI: 10.1038/s41467-020-18735-8

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