Hippo/MST blocks breast cancer by downregulating WBP2 oncogene expression via miRNA processor Dicer

• Published in: Cell death & disease Vol. 11; no. 8; p. 669
• Main Authors: Lim, Shen Kiat, Tabatabaeian, Hossein, Lu, Ssu Yi, Kang, Shin-Ae, Sundaram, Gopinath Meenakshi, Sampath, Prabha, Chan, Siew Wee, Hong, Wan Jin, Lim, Yoon Pin
• Format: Journal Article
• Language: English
• Published: England Springer Nature B.V 21.08.2020; Nature Publishing Group UK
• Subjects: 3' Untranslated regions; Adaptor Proteins, Signal Transducing - genetics; Breast cancer; Breast Neoplasms - metabolism; Cell Line, Tumor; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Gene Expression - genetics; Gene Expression Regulation, Neoplastic - genetics; Humans; Kinases; Localization; Lysosomes; MAP Kinase Kinase Kinases - metabolism; MAP Kinase Kinase Kinases - physiology; MCF-7 Cells; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Oncogene Proteins - genetics; Oncogenes; Phosphorylation; Post-translation; Precision medicine; Proteasomes; Protein interaction; Protein turnover; Protein-Serine-Threonine Kinases - metabolism; Protein-Serine-Threonine Kinases - physiology; Proteins; Ribonuclease III - genetics; Ribonuclease III - metabolism; Signal transduction; Signal Transduction - genetics; Trans-Activators - metabolism; Trans-Activators - physiology; Transcription activation; Transcription Factors - metabolism; Tumor cell lines; Tumor suppressor genes; Tumorigenesis; Ubiquitination; Wnt protein; Wnt Signaling Pathway; Xenografts; Yes-associated protein
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-02901-3

WBP2 transcription coactivator is an emerging oncoprotein and a key node of convergence between EGF and Wnt signaling pathways. Understanding how WBP2 is regulated has important implications for cancer therapy. WBP2 is tightly controlled by post-translational modifications, including phosphorylation and ubiquitination, leading to changes in subcellular localization, protein-protein interactions, and protein turnover. As the function of WBP2 is intricately linked to YAP and TAZ, we hypothesize that WBP2 is negatively regulated by the Hippo tumor suppressor pathway. Indeed, MST is demonstrated to negatively regulate WBP2 expression in a kinase-dependent but LATS-independent manner. This was observed in the majority of the breast cancer cell lines tested. The effect of MST was enhanced by SAV and concomitant with the inhibition of the transcription co-activation, in vitro and in vivo tumorigenesis activities of WBP2, resulting in good prognosis in xenografts. Downregulation of WBP2 by MST involved miRNA but not proteasomal or lysosomal degradation. Our data support the existence of a novel MST-Dicer signaling axis, which in turn regulates both WBP2 CDS- and UTR-targeting miRNAs expression, including miR-23a. MiR-23a targets the 3'UTR of WBP2 mRNA directly. Significant inverse relationships between WBP2 and MST or miR23a expression levels in clinical specimens were observed. In conclusion, WBP2 is a target of the Hippo/MST kinase; MST is identified as yet another rheostat in the regulation of WBP2 and its oncogenic function. The findings have implications in targeted therapeutics and precision medicine for breast cancer.