Musashi-1 promotes stress-induced tumor progression through recruitment of AGO2

Hsiao Yun Chen, Mong Lien Wang, Benoit Laurent, Dr Chih Hung Hsu, Ming Teh Chen, Liang Ting Lin, Jia Shen, Wei Chao Chang, Jennifer Hsu, Mien Chie Hung, Yi Wei Chen, Pin I. Huang, Yi Ping Yang, Chung Pin Li, Hsin I. Ma, Chung Hsuan Chen, Wen Chang Lin, Shih Hwa Chiou

Research output: Journal article publicationJournal articleAcademic researchpeer-review

3 Citations (Scopus)

Abstract

Carcinomatous progression and recurrence are the main therapeutic challenges frequently faced by patients with refractory tumors. However, the underlined molecular mechanism remains obscure. Methods: We found Musashi-1 (MSI1) transported into cytosol under stress condition by confocal microscopy and cell fractionation. Argonaute 2 (AGO2) was then identified as a cytosolic binding partner of MSI1 by Mass Spectrametry, immunoprecipitation, and recombinant protein pull-down assay. We used RNA-IP to determine the MSI1/AGO2 associated regions on downstream target mRNAs. Finally, we overexpressed C-terminus of MSI1 to disrupt endogenous MSI1/AGO2 interaction and confirm it effects on tmor progression. Results: Malignant tumors exhibit elevated level of cytosolic Musashi-1 (MSI1), which translocates into cytosol in response to stress and promote tumor progression. Cytosolic MSI1 forms a complex with AGO2 and stabilize or destabilize its target mRNAs by respectively binding to their 3´ untranslated region or coding domain sequence. Both MSI1 translocation and MSI1/AGO2 binding are essential for promoting tumor progression. Blocking MSI1 shuttling by either chemical inhibition or point mutation attenuates the growth of GBM-xenografts in mice. Importantly, overexpression of the C-terminus of MSI1 disrupts endogenous MSI1/AGO2 interaction and effectively reduces stress-induced tumor progression. Conclusion: Our findings highlight novel molecular functions of MSI1 during stress-induced carcinomatous recurrence, and suggest a new therapeutic strategy for refractory malignancies by targeting MSI1 translocation and its interaction with AGOs.

Original languageEnglish
Pages (from-to)201-217
Number of pages17
JournalTheranostics
Volume10
Issue number1
DOIs
Publication statusPublished - 1 Jan 2020
Externally publishedYes

Keywords

  • Argonaute 2
  • Cancer
  • Musashi-1
  • RNA regulation
  • Subcellular translocation
  • Tumor recurrence

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

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