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.
Highlights
Breast cancer remains the most prevalent and the leading cause of cancer-related deaths in women worldwide [1]
The results show that DiGeorge Critical Region 8 (DGCR8), DEAD-box helicase 5 (DDX5), and DEAD-Box Helicase17 (DDX17) individually correlated with higher relapse-free survival in breast cancer, hazard ratio (HR) = 0.78, HR = 0.72, HR = 0.66, respectively (Fig 6D–F)
Besides regulation at the posttranslational and transcriptional levels, WW domain-binding protein 2 (WBP2) transcripts are tightly regulated posttranscriptionally by miRNAs, such as miR-206 [15], miR-613 [11], and miR-23a [16] in breast cancer, and miR-485 in hepatocellular carcinoma [17]. Beyond these WBP2 39UTR-targeting miRNAs, we recently showed that WBP2 is negatively regulated by coding DNA sequencetargeting miRNAs as well
Summary
Breast cancer remains the most prevalent and the leading cause of cancer-related deaths in women worldwide [1]. There are about 2.1 million newly diagnosed breast cancer cases in females annually, which accounts for roughly a quarter of cancer cases among women [1]. The expression of WBP2 correlates positively and significantly with tumor size and grade, and negatively with disease-free and overall survival of breast cancer patients including those with HER2positive breast cancer [2, 3]. These data highlight the importance of WBP2 to early development of breast cancer and its aggression
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
