MSI2 promotes translation of multiple IRES-containing oncogenes and virus to induce self-renewal of tumor initiating stem-like cells

Da-Wei Yeh; Xuyao Zhao; Hifzur R Siddique; Mengmei Zheng; Hye Yeon Choi; Tatsuya Machida; Padmini Narayanan; Yi Kou; Vasu Punj; Stanley M Tahara; Douglas E Feldman; Lin Chen; Keigo Machida

doi:10.1038/s41420-023-01427-9

MSI2 promotes translation of multiple IRES-containing oncogenes and virus to induce self-renewal of tumor initiating stem-like cells

Cell Death Discov. 2023 Apr 28;9(1):141. doi: 10.1038/s41420-023-01427-9.

Authors

Da-Wei Yeh^#¹, Xuyao Zhao^#¹, Hifzur R Siddique^#^{1

2}, Mengmei Zheng¹, Hye Yeon Choi¹, Tatsuya Machida¹, Padmini Narayanan¹, Yi Kou³, Vasu Punj⁴, Stanley M Tahara¹, Douglas E Feldman¹, Lin Chen³, Keigo Machida^{5

6}

Affiliations

¹ Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, 90033, USA.
² Molecular Cancer Genetics & Translational Research Lab, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh, 202002, India.
³ Viterbi School of Engineering, University of Southern California, Los Angeles, 90089, USA.
⁴ Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, 90033, USA.
⁵ Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, 90033, USA. keigo.machida@med.usc.edu.
⁶ Southern California Research Center for ALPD and Cirrhosis, Los Angeles, 90033, USA. keigo.machida@med.usc.edu.

^# Contributed equally.

Abstract

RNA-binding protein Musashi 2 (MSI2) is elevated in several cancers and is linked to poor prognosis. Here, we tested if MSI2 promotes MYC and viral mRNA translation to induce self-renewal via an internal ribosome entry sequence (IRES). We performed RIP-seq using anti-MSI2 antibody in tumor-initiating stem-like cells (TICs). MSI2 binds the internal ribosome entry site (IRES)-containing oncogene mRNAs including MYC, JUN and VEGFA as well as HCV IRES to increase their synthesis and promote self-renewal and tumor-initiation at the post-transcriptional level. MSI2 binds a lncRNA to interfere with processing of a miRNA that reduced MYC translation in basal conditions. Deregulation of this integrated MSI2-lncRNA-MYC regulatory loop drives self-renewal and tumorigenesis through increased IRES-dependent translation of MYC mRNA. Overexpression of MSI2 in TICs promoted their self-renewal and tumor-initiation properties. Inhibition of MSI2-RNA binding reduced HCV IRES activity, viral replication and liver hyperplasia in humanized mice predisposed by virus infection and alcohol high-cholesterol high-fat diet. Together MSI2, integrating the MYC oncogenic pathway, can be employed as a therapeutic target in the treatment of HCC patients. A hypothetical model shows that MSI2 binds and activates cap-independent translation of MYC, c-JUN mRNA and HCV through MSI2-binding to Internal Ribosome Entry Sites (IRES) resulting in upregulated MYC, c-JUN and viral protein synthesis and subsequent liver oncogenesis. Inhibitor of the interaction between MYC IRES and MSI2 reduces liver hyperplasia, viral mRNA translation and tumor formation.

Abstract

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