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

Abstract

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 LATSindependent 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.

WBP2 negatively regulates the Hippo pathway by competitively binding to WWC3 with LATS1 to promote non-small cell lung cancer progression

“…However, the underlying cause of high WBP2 expression in lung cancer remains unclear. Based on existing literature, WBP2 expression could be affected by several underlying factors, including non-coding micro-RNA 30 , transcriptional factors 31 , and ITCH 32 , as well as some classical signaling transduction pathway activities 33 . These experimental data have helped clarify the reasons for high WBP2 expression in different tumors.…”

WBP2 Negatively Regulates Hippo Pathway By Competitively Binding To WWC3 With LATS1 To Promote The Malignant Phenotype Of Non-Small Cell Lung Cancer

“…Additionally, changes in the activity of some classic signaling pathways can play an important role in regulating the expression of WBP2. For example, MST in the Hippo pathway can regulate the expression of WBP2 through the miRNA-Dicer pathway in a kinase-dependent manner [34].…”

“…The molecular mechanism underlying the function of WBP2 in breast cancer is closely related to the steroid hormone signaling pathway (ER-based). Some scholars have determined that WBP2 is also the key node of the PI3K and Wnt signaling transduction pathways in other tumors [14,18,29], and WBP2 also plays a key role in the Hippo pathway [34]. Both Yki/YAP and TAZ in the Hippo signaling pathway are vital binding proteins of WBP2, as the binding of these proteins facilitates the transcription of downstream target genes and affects the development of Drosophila and the proliferation and invasion of tumor cells [8-9, 16, 19-20].…”

WBP2 inhibits microRNA biogenesis via interaction with the microprocessor complex

“…A number of miRNAs have also been identified to regulate WBP2 at the post-transcriptional level. For example, the 39UTR region of WBP2 has been demonstrated to be targeted by miR-206, miR-613, and miR-23a in breast cancer (11,15,16), and miR-458 in hepatocellular carcinoma (17).…”

“…In addition to these core components, a number of auxiliary molecules have been recently reported to be important in the processing of Pri-miRNAs into Pre-miRNAs, for example, BRCA1 (23), Smads (24), Myc (25), and p53 (26). Recently, our laboratory showed that WBP2 is regulated by both 39UTR and coding DNA sequence-targeting miRNAs and that Dicer or DGCR8 modulates WBP2 expression under the influence of mammalian sterile 20-like (MST)/Hippo signaling (16). Taken together, we hypothesize that WBP2 regulates miRNA biogenesis via a negative feedback loop.…”