Transcriptional regulation and ubiquitination-dependent regulation of HnRNPK oncogenic function in prostate tumorigenesis.

BACKGROUND: Heterogeneous nuclear ribonucleoprotein K (HnRNPK) is a nucleic acid-binding protein that regulates diverse biological events. Pathologically, HnRNPK proteins are frequently overexpressed and clinically correlated with poor prognosis in various types of human cancers and are therefore pursued as attractive therapeutic targets for select patients. However, both the transcriptional regulation and degradation of HnRNPK in prostate cancer remain poorly understood. METHODS: qRT-PCR was used to detect the expression of HnRNPK mRNA and miRNA; Immunoblots and immunohistochemical assays were used to determine the levels of HnRNPK and other proteins. Flow cytometry was used to investigate cell cycle stage. MTS and clonogenic assays were used to investigate cell proliferation. Immunoprecipitation was used to analyse the interaction between SPOP and HnRNPK. A prostate carcinoma xenograft mouse model was used to detect the in vivo effects of HnRNPK and miRNA. RESULTS: In the present study, we noted that HnRNPK emerged as an important player in the carcinogenesis process of prostate cancer. miR-206 and miR-613 suppressed HnRNPK expression by targeting its 3'-UTR in PrCa cell lines in which HnRNPK is overexpressed. To explore the potential biological function, proliferation and colony formation of PrCa cells in vitro and tumor growth in vivo were also dramatically suppressed upon reintroduction of miR-206/miR-613. We have further provided evidence that Cullin 3 SPOP is a novel upstream E3 ubiquitin ligase complex that governs HnRNPK protein stability and oncogenic functions by promoting the degradation of HnRNPK in polyubiquitination-dependent proteolysis in the prostate cancer setting. Moreover, prostate cancer-associated SPOP mutants fail to interact with and promote the destruction of HnRNPK proteins. CONCLUSION: Our findings reveal new posttranscriptional and posttranslational modification mechanisms of HnRNPK regulation via miR-206/miR-613 and SPOP, respectively. More importantly, given the critical oncogenic role of HnRNPK and the high frequency of SPOP mutations in prostate cancer, our results provide a molecular rationale for the clinical investigation of novel strategies to combat prostate cancer based on SPOP genetic status.

Research on the Relationship Between Informational Team Faultline and Team Resilience-Team Leader Member Exchange and Team Member Exchange as Mechanism.

Background: This study aims to investigate how a team can be resilient in the face of crisis and adversity. Methods: This empirical study adopted a quantitative research method. The data were collected by questionnaire survey, and the stats analysis package in R language and AMOS 23 were used for empirical analysis of 98 teams. Based on complex adaptive system theory and conservation of resources theory, this study was constructed the theoretical framework of "environmental influence - team exchange - team resilience" with informational team faultline (ITF) as independent variable, team leader member exchange (TLMX) and team member exchange (TMX) as mediating and moderating variables, and team resilience as dependent variable in the context of Chinese culture. Results: We found that the ITF had a significant negative effect on the team resilience. TLMX and TMX played partial mediating role between ITF and team resilience. In addition, TLMX and TMX played moderating role between ITF and team resilience, that is, weakening the negative influence of ITF on team resilience. Conclusion: This study contributes to clarify the mechanism of the influence of ITF on team resilience, and provide reference for team leaders to improve team resilience in the face of adversity.

Exploiting E3 ubiquitin ligases to reeducate the tumor microenvironment for cancer therapy.

Tumor development relies on a complex and aberrant tissue environment in which cancer cells receive the necessary nutrients for growth, survive through immune escape, and acquire mesenchymal properties that mediate invasion and metastasis. Stromal cells and soluble mediators in the tumor microenvironment (TME) exhibit characteristic anti-inflammatory and protumorigenic activities. Ubiquitination, which is an essential and reversible posttranscriptional modification, plays a vital role in modulating the stability, activity and localization of modified proteins through an enzymatic cascade. This review was motivated by accumulating evidence that a series of E3 ligases and deubiquitinases (DUBs) finely target multiple signaling pathways, transcription factors and key enzymes to govern the functions of almost all components of the TME. In this review, we systematically summarize the key substrate proteins involved in the formation of the TME and the E3 ligases and DUBs that recognize these proteins. In addition, several promising techniques for targeted protein degradation by hijacking the intracellular E3 ubiquitin-ligase machinery are introduced.

Novel insights into the SPOP E3 ubiquitin ligase: From the regulation of molecular mechanisms to tumorigenesis.

Ubiquitin-mediated protein degradation is the primary biological process by which protein abundance is regulated and protein homeostasis is maintained in eukaryotic cells. Speckle-type pox virus and zinc finger (POZ) protein (SPOP) is a typical substrate adaptor of the Cullin 3-RING ligase (CRL3) family; it serves as a bridge between the Cullin 3 (Cul3) scaffold protein and its substrates. In recent years, SPOP has received increasing attention because of its versatility in its regulatory pathways and the diversity of tumor types involved. Mechanistically, SPOP substrates are involved in a wide range of biological processes, and abnormalities in SPOP function perturb downstream biological processes and promote tumorigenesis. Additionally, liquid-liquid phase separation (LLPS), a potential mechanism of membraneless organelle formation, was recently found to mediate the self-triggered colocalization of substrates with higher-order oligomers of SPOP. Herein, we summarize the structure of SPOP and the specific mechanisms by which it mediates the efficient ubiquitination of substrates. Additionally, we review the biological functions of SPOP, the regulation of SPOP expression, the role of SPOP in tumorigenesis and its therapeutic value.