The canonical Wnt/β-catenin signaling pathway plays a central role in development and cancer. The p21-activated kinase 4 (PAK4) involves in a wide range of cellular processes, including cytoskeletal reorganization, cell proliferation, gene transcription and oncogenic transformation. However, the cross talk between the Wnt and PAK4 signaling pathways is poorly understood. Here, we show that PAK4 is a nucleo-cytoplasmic shuttling protein, containing three nuclear export signals (NESs) and two nuclear localization signals (NLSs). PAK4 is exported by the chromosome region maintenance-1 (CRM-1)-dependent pathway and is imported into the nucleus in an importin α5-dependent manner. PAK4 interacts with and phosphorylates β-catenin on Ser675, which promotes the TCF/LEF transcriptional activity and stabilizes β-catenin through inhibition of its degradation. Moreover, nuclear import of PAK4 accompanies with the nuclear import of β-catenin and increased TCF/LEF transcriptional activity. We further demonstrated that PAK4 associates with the TCF/LEF transcriptional complex by ChIP assays. These findings uncover a novel role for PAK4 in modulating intracellular translocation and signaling of β-catenin.

PurposeAlthough the mental health status of doctoral students deserves attention, few scholars have paid attention to factors related to their mental health problems. We aimed to investigate the prevalence of depression and anxiety in doctoral students and examine possible associated factors. We further aimed to assess whether mentoring relationships mediate the association between research self-efficacy and depression/anxiety.MethodsA cross-sectional study was conducted among 325 doctoral students in a medical university. The Patient Health Questionnaire 9 and Generalized Anxiety Disorder 7 scale were used to assess depression and anxiety. The Research Self-Efficacy Scale was used to measure perceived ability to fulfill various research-related activities. The Advisory Working Alliance Inventory-student version was used to assess mentoring relationships. Linear hierarchical regression analyses were performed to determine if any factors were significantly associated with depression and anxiety. Asymptotic and resampling methods were used to examine whether mentoring played a mediating role.ResultsApproximately 23.7% of participants showed signs of depression, and 20.0% showed signs of anxiety. Grade in school was associated with the degree of depression. The frequency of meeting with a mentor, difficulty in doctoral article publication, and difficulty in balancing work–family–doctoral program was associated with both the level of depression and anxiety. Moreover, research self-efficacy and mentoring relationships had negative relationships with levels of depression and anxiety. We also found that mentoring relationships mediated the correlation between research self-efficacy and depression/anxiety.ConclusionThe findings suggest that educational experts should pay close attention to the mental health of doctoral students. Active strategies and interventions that promote research self-efficacy and mentoring relationships might be beneficial in preventing or reducing depression and anxiety.

Carbonic anhydrase IX (CAIX) plays an important role in the growth and survival of tumor cells. MORC2 is a member of the MORC protein family. The MORC proteins contain a CW-type zinc finger domain and are predicted to have the function of regulating transcription, but no MORC2 target genes have been identified. Here we performed a DNA microarray hybridization and found CAIX mRNA to be down-regulated 8-fold when MORC2 was overexpressed. This result was further confirmed by northern and western blot analysis. Our results also showed that the protected region 4 (PR4) was important for the repression function of MORC2. Moreover, MORC2 decreased the acetylation level of histone H3 at the CAIX promoter. Meanwhile, trichostatin A (TSA) had an increasing effect on CAIX promoter activity. Among the six HDACs tested, histone deacetylase 4 (HDAC4) had a much more prominent effect on CAIX repression. ChIP and ChIP Re-IP assays showed that MORC2 and HDAC4 were assembled on the same region of the CAIX promoter. Importantly, we further confirmed that both proteins are simultaneously present in the PR4-binding complex. These results may contribute to understanding the molecular mechanisms of CAIX regulation.

The p21-activated kinase 4 (PAK4) is overexpressed in different cancers and promotes proliferation of cancer cells. Reprogramming of glucose metabolism is found in most cancer cells which in turn supports rapid proliferation. However, the relationship between PAK4 and glucose metabolism in cancer cells has not been explored. In this study, we reported that PAK4 promoted glucose intake, NADPH production and lipid biosynthesis, leading to an increased proliferation of colon cancer cells. Mechanistically, PAK4 interacted with glucose-6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme of the pentose phosphate pathway and increased G6PD activity via enhancing Mdm2-mediated p53 ubiquitination degradation. In addition, we demonstrated a close positive correlation between PAK4 and G6PD expression in colon cancer specimens. Furthermore, expression of PAK4 or G6PD was positively correlated with an aggressive phenotype of clinical colon cancer. These findings revealed a novel glucose metabolism-related mechanism of PAK4 in promoting colon cancer cell growth, suggesting that PAK4 and/or G6PD blockage might be a potential therapeutic strategy for colon cancer.

Epithelial-mesenchymal transition (EMT) is a key process in tumor metastatic cascade that is characterized by the loss of cell-cell junctions, resulting in the acquisition of migratory and invasive properties. E-cadherin is a major component of intercellular junctions and the reduction or loss of its expression is a hallmark of EMT. Transcription factor GATA1 has a critical anti-apoptotic role in breast cancer, but its function for metastasis has not been investigated. Here, we found that GATA1, as a novel E-cadherin repressor, promotes EMT in breast cancer cells. GATA1 binds to E-cadherin promoter, down-regulates E-cadherin expression, disrupts intercellular junction and promotes metastasis of breast cancer cell in vivo. Moreover, GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. Our findings provide insights into the novel function of GATA1, contributing to a better understanding of the EMT, indicating that GATA1 and its phosphorylation may play an important role in the metastasis of breast cancer.