Programmed cell death 5 mediates HDAC3 decay to promote genotoxic stress response

The inhibition of p53 activity by histone deacetylase 3 (HDAC3) has been reported, but the precise molecular mechanism is unknown. Here we show that programmed cell death 5 (PDCD5) selectively mediates HDAC3 dissociation from p53, which induces HDAC3 cleavage and ubiquitin-dependent proteasomal degradation. Casein kinase 2 alpha phosphorylates PDCD5 at Ser-119 to enhance its stability and importin 13-mediated nuclear translocation of PDCD5. Genetic deletion of PDCD5 abrogates etoposide (ET)-induced p53 stabilization and HDAC3 cleavage, indicating an essential role of PDCD5 in p53 activation. Restoration of PDCD5(WT) in PDCD5(-/-) MEFs restores ET-induced HDAC3 cleavage. Reduction of both PDCD5 and p53, but not reduction of either protein alone, significantly enhances in vivo tumorigenicity of AGS gastric cancer cells and correlates with poor prognosis in gastric cancer patients. Our results define a mechanism for p53 activation via PDCD5-dependent HDAC3 decay under genotoxic stress conditions.ope

Wntless/GPR177 표적치료를 통한 위암 형성의 억제 및 작용 기전 규명

Wntless/GPR177 functions as WNT ligand carrier protein and activator of WNT/β-catenin signaling, however, its role in gastric tumorigenesis has remained elusive. We investigated the role of GPR177 in gastric tumorigenesis and provided the therapeutic potential of a clinical development of anti-GPR177 antibodies. GPR177 mRNA and protein expression were associated with unfavorable prognosis [log-rank test, GSE15459 (p=0.00736), GSE66229 (p=0.0142), and Yonsei TMA (p=0.0334)] and identified as an independent risk predictor of clinical outcomes {GSE15459 [hazard ratio (HR) 1.731 (95% confidence interval; CI; 1.103–2.715), p=0.017], GSE66229 [HR 1.54 (95% CI, 1.10–2.151), p=0.011], and Yonsei TMA [HR 1.254 (95% CI, 1.049–1.500), p=0.013]. Overall survival and multivariate prognostic significance of GPR177 expression were analyzed by Kaplan-Meier curves (log-rank test) and Cox proportional hazard regression models, respectively. GC cell lines were classified as WNT-secreting or non–WNT-secreting. Anti-GPR177 antibody reduced WNT secretion and viability in WNT-secreting cells by inhibition of WNT/β-catenin signaling. GPR177 alleviated ER–stress-induced apoptosis by ectopic localization to ER in non–WNT-secreting cells. Antibody treatment suppressed proliferation of WNT-secreting cells only; however, GPR177 knockdown sensitized non–WNT-secreting cells to ER–stress-induced apoptosis. Anti-GPR177 antibodies exhibited anti-cancer efficacy in xenograft and PDX models. GPR177 overexpression correlated with poor GC patient prognosis. Inhibition of GPR177 using monoclonal antibodies or short–hairpin–RNA-mediated knockdown suppresses in vitro and in vivo tumorigenesis in WNT-secreting GC cells and inhibits WNT/β-catenin signaling. Non–WNT-secreting cells were sensitized by GPR177 knockdown, but not by antibody treatment, via enhancement of ER stress, leading to cell death. Anti-GPR177 antibody treatment suppresses in vivo gastric tumorigenesis.open박

YAF2 promotes TP53-mediated genotoxic stress response via stabilization of PDCD5

Programmed cell death 5 (PDCD5) plays a crucial role in TP53-mediated apoptosis, but the regulatory mechanism of PDCD5 itself during apoptosis remains obscure. We identified YY1-associated factor 2 (YAF2) as a novel PDCD5-interacting protein in a yeast two-hybrid screen for PDCD5-interacting proteins. We found that YY1-associated factor 2 (YAF2) binds to and increases PDCD5 stability by inhibiting the ubiquitin-dependent proteosomal degradation pathway. However, knocking-down of YAF2 diminishes the levels of PDCD5 protein but not the levels of PDCD5 mRNA. Upon genotoxic stress response, YAF2 promotes TP53 activation via association with PDCD5. Strikingly, YAF2 failed to promote TP53 activation in the deletion of PDCD5, whereas restoration of wild-type PDCD5WT efficiently reversed the ineffectiveness of YAF2 on TP53 activation. Conversely, PDCD5 efficiently overcame the knockdown effect of YAF2 on ET-induced TP53 activation. Finally, impaired apoptosis upon PDCD5 ablation was substantially rescued by restoration of PDCD5WT but not YAF2-interacting defective PDCD5E4D nor TP53-interacting defective PDCD5E16D mutant. Our findings uncovered an apoptotic signaling cascade linking YAF2, PDCD5, and TP53 during genotoxic stress responses.ope

DNAJB1 negatively regulates MIG6 to promote epidermal growth factor receptor signaling

Mitogen-inducible gene 6 (MIG6) is a tumor suppressor implicated in the development of human cancers; however, the regulatory mechanisms of MIG6 remain unknown. Here, using a yeast two-hybrid screen, we identified DnaJ homolog subfamily B member I (DNAJB1) as a novel MIG6-interacting protein. We found that DNAJB1 binds to and decreases MIG6 protein, but not mRNA, levels. DNAJB1 overexpression dosage-dependently decreased MIG6 protein levels. Conversely, DNAJB1 knockdown increased MIG6 protein levels. DNAJB1 destabilizes MIG6 by enhancing K48-linked ubiquitination of MIG6. However, knocking-down of DNAJB1 reduced the ubiquitination of MIG6. DNAJB1 positively regulates the epidermal growth factor receptors (EGFR) signaling pathway via destabilization of MIG6; however, DNAJB1 knockdown diminishes activation of EGFR signaling as well as elevation of MIG6. Importantly, the increased levels of MIG6 by DNAJB1 knockdown greatly enhanced the gefitinib sensitivity in A549 cells. Thus, our study provides a new molecular mechanism to regulate EGFR signaling through modulation of MIG6 by DNAJB1 as a negative regulator.ope