WBP2 inhibits microRNA biogenesis via interaction with the microprocessor complex

Abstract

WBP2 is an emerging oncoprotein with diverse functions in breast tumorigenesis via regulating Wnt, epidermal growth factor receptor, estrogen receptor, and Hippo. Recently, evidence shows that WBP2 is tightly regulated by the components of the miRNA biogenesis machinery such as DGCR8 and Dicer via producing both WBP2’s 3′UTR and coding DNA sequence-targeting miRNAs. This led us to hypothesize that WBP2 could provide a feedback loop to the biogenesis of its key upstream regulators by regulating the microprocessor complex activity. Indeed, WBP2 suppressed microprocessor activity by blocking the processing of pri-miRNAs to pre-miRNAs. WBP2 negatively regulated the assembly of the microprocessor complex via physical interactions with its components. Meta-analyses suggest that microprocessor complex components, in particular DGCR8, DDX5, and DEAD-Box Helicase17 (DDX17), have tumor-suppressive properties. 2D and 3D in vitro proliferation assays revealed that WBP2 blocked the tumor-suppressive properties of DGCR8, a key component of the microprocessor complex. In conclusion, WBP2 is a novel regulator of miRNA biogenesis that is a known dysregulated pathway in breast tumorigenesis. The reregulation of miRNA biogenesis machinery via targeting WBP2 protein may have implications in breast cancer therapy.

WW domain binding protein 2 (WBP2) as an oncogene in breast cancer: mechanisms and therapeutic prospects—a narrative review

“…There is also a reverse regulatory mechanism for the biogenesis process of miRNAs by WBP2. As demonstrated by Tabatabaeian et al , DiGeorge Critical Region 8 (DGCR8) is an essential component of the microprocessor complex, of which the oncogenic properties are inhibited by WBP2, leading to the disruption of downstream mature miRNA formation ( 21 ). The mechanism of this process is still unclear.…”

Reciprocal Regulation of Hippo and WBP2 Signalling—Implications in Cancer Therapy

“…This led to the disassembly of MPC and a reduction in its miRNA processing capacity, as confirmed by biochemical MPC assays. Despite the fact that several MPC factors such as DGCR8 contain the WW domain, the PY motifs of WBP2 were not responsible for association with the MPC [83]. The exact mechanism underlying WBP2's interaction with the MPC components remains to be investigated.…”

“…In lung and gastric cancers, WBP2 has been shown to be a promoter of LATS1/2 kinase activities through interactions with critical regulatory components to inactivate Hippo signalling [71,72]. Secondly, WBP2 may be involved in microRNA (miRNA) pre-processing by disrupting the formation of the microprocessor complex (MPC) [83]. The miRNAs are small single-stranded non-coding RNAs that are known to play an important role in regulating gene expression.…”

“…On the other hand, WBP2 could impair the miRNA biogenesis process through the disruption of the MPC complex in the nucleus [83]. As a result, WBP2-targeting miRNAs were also inhibited [83].…”

“…On the other hand, WBP2 could impair the miRNA biogenesis process through the disruption of the MPC complex in the nucleus [83]. As a result, WBP2-targeting miRNAs were also inhibited [83]. Immunoprecipitation experiments in multiple breast cancer cell lines revealed the interaction of WBP2 with several MPC components, such as DGCR8, Drosha, DDX5 and DDX17.…”