Pleiotropic tumor suppressor functions of WWOX antagonize metastasis

Saleh Khawaled, Giovanni Nigita, Rosario Distefano, Sara Oster, Sung Suk Suh, Yoav Smith, Abed Khalaileh, Yong Peng, Carlo M. Croce, Tamar Geiger, Victoria L. Seewaldt, Rami I. Aqeilan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Tumor progression and metastasis are the major causes of death among cancer associated mortality. Metastatic cells acquire features of migration and invasion and usually undergo epithelia-mesenchymal transition (EMT). Acquirement of these various hallmarks rely on different cellular pathways, including TGF-β and Wnt signaling. Recently, we reported that WW domain-containing oxidoreductase (WWOX) acts as a tumor suppressor and has anti-metastatic activities involving regulation of several key microRNAs (miRNAs) in triple-negative breast cancer (TNBC). Here, we report that WWOX restoration in highly metastatic MDA-MB435S cancer cells alters mRNA expression profiles; further, WWOX interacts with various proteins to exert its tumor suppressor function. Careful alignment and analysis of gene and miRNA expression in these cells revealed profound changes in cellular pathways mediating adhesion, invasion and motility. We further demonstrate that WWOX, through regulation of miR-146a levels, regulates SMAD3, which is a member of the TGF-β signaling pathway. Moreover, proteomic analysis of WWOX partners revealed regulation of the Wnt-signaling activation through physical interaction with Disheveled. Altogether, these findings underscore a significant role for WWOX in antagonizing metastasis, further highlighting its role and therapeutic potential in suppressing tumor progression.

Original languageEnglish
Article number43
JournalSignal Transduction and Targeted Therapy
Issue number1
StatePublished - 1 Dec 2020


FundersFunder number
ICRF-City of Hope - Harvey L. Miller Family Foundation
Israel Cancer Research Fund
Horizon 2020 Framework Programme682118
European Research Council
Israel Science Foundation15/ 1574


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