RNA-binding protein NONO contributes to cancer cell growth and confers drug resistance as a theranostic target in TNBC

Seong Jin Kim, Jin Sung Ju, Myoung Hee Kang, Ji Won Eun, Young Ha Kim, Prahlad V. Raninga, Kum Kum Khanna, Balázs Győrffy, Chan Gi Pack, Hee Dong Han, Hee Jin Lee, Gyungyub Gong, Yong Shin, Gordon B. Mills, Seong Il Eyun, Yun Yong Park

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Breast cancer (BC) is one of the most common cancers in women. TNBC (Triple-negative breast cancer) has limited treatment options and still lacks viable molecular targets, leading to poor outcomes. Recently, RNA-binding proteins (RBPs) have been shown to play crucial roles in human cancers, including BC, by modulating a number of oncogenic phenotypes. This suggests that RBPs represent potential molecular targets for BC therapy. Methods: We employed genomic data to identify RBPs specifically expressed in TNBC. NONO was silenced in TNBC cell lines to examine cell growth, colony formation, invasion, and migration. Gene expression profiles in NONO-silenced cells were generated and analyzed. A high-throughput screening for NONO-targeted drugs was performed using an FDA-approved library. Results: We found that the NONO RBP is highly expressed in TNBC and is associated with poor patient outcomes. NONO binds to STAT3 mRNA, increasing STAT3 mRNA levels in TNBC. Surprisingly, NONO directly interacts with STAT3 protein increasing its stability and transcriptional activity, thus contributing to its oncogenic function. Importantly, high-throughput drug screening revealed that auranofin is a potential NONO inhibitor and inhibits cell growth in TNBC. Conclusions: NONO is an RBP upstream regulator of both STAT3 RNA and protein levels and function. It represents an important and clinically relevant promoter of growth and resistance of TNBCs. NONO is also therefore a potential therapeutic target in TNBC.

Original languageEnglish
Pages (from-to)7974-7992
Number of pages19
JournalTheranostics
Volume10
Issue number18
DOIs
Publication statusPublished - 2020

Bibliographical note

Funding Information:
We thank the Confocal Microscope and HTS core facility at the ConveRgence mEDIcine research cenTer (CREDIT), Asan Institute for Life Sciences, for support and instrumentation. This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI17C0380 to Y-Y.P.), by a National Research Foundation of Korea Grant (NRF-2020R1A2C1003216) to Y-Y.P, and was additionally supported by a National Research Foundation of Korea Grant (2018R1C1B3001650) to SE.

Funding Information:
This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI17C0380 to Y-Y.P.), by a National Research Foundation of Korea Grant (NRF-2020R1A2C1003216) to Y-Y.P, and was additionally supported by a National Research Foundation of Korea Grant (2018R1C1B3001650) to SE.

Publisher Copyright:
© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

All Science Journal Classification (ASJC) codes

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

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