scholarly journals WD repeat domain 5 promotes chemoresistance and Programmed Death-Ligand 1 expression in prostate cancer

Theranostics ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 4809-4824
Author(s):  
Qianghua Zhou ◽  
Xu Chen ◽  
Haixia He ◽  
Shengmeng Peng ◽  
Yangjie Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
Repeat Domain ◽  
Wd Repeat

scholarly journals Targeting WD repeat domain 5 enhances chemosensitivity and inhibits proliferation and programmed death-ligand 1 expression in bladder cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Jingtong Zhang ◽  
Qianghua Zhou ◽  
Keji Xie ◽  
Liang Cheng ◽  
Shengmeng Peng ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Immune Evasion ◽  
Dependent Manner ◽  
Histologic Subtype ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
Repeat Domain ◽  
Wd Repeat

Abstract Background Chemotherapy and/or immunotherapy are first-line treatments for advanced muscle-invasive bladder cancer (BCa), but the unsatisfactory objective response rate to these treatments yields poor 5-year patient survival. Discovery of therapeutic targets essential for BCa maintenance is critical to improve therapy response in clinic. This study evaluated the role of targeting WD repeat domain 5 (WDR5) with the small molecule compound OICR-9429 and whether it could be used to treat bladder cancer. Methods We analysed the expression and clinical prognosis of WDR5 in a TCGA cohort. The pharmacological role of OICR-9429 was further investigated in vitro and in vivo. RNA sequencing, western blot, and chromatin immunoprecipitation (ChIP) were utilized to explored the mechanism underlying OICR-9429-induced WDR5 inhibition. Results First, we found that WDR5 expression was upregulated in BCa and was associated with histologic grade, metastasis status, histologic subtype, and molecular subtype. High WDR5 expression level was also correlated with shorter overall survival (OS) in BCa. The WDR5 inhibitor OICR-9429 reduced cell viability by decreasing H3K4me3 levels but not WDR5 levels in T24, UM-UC-3, and TCCSUP BCa cells. OICR-9429 suppressed the proliferation of BCa cells by blocking the G1/S phase transition. Next, OICR-9429 enhanced apoptosis and chemosensitivity to cisplatin in BCa cells. In addition, OICR-9429 independently inhibited the motility and metastatic behaviour of BCa cells. In vivo experiments further revealed that OICR-9429 suppressed tumour growth, enhanced chemosensitivity, and reduced the toxicity of cisplatin in BCa. Notably, WDR5 was positively correlated with programmed death-ligand 1 (PD-L1) expression, and OICR-9429 suppressed immune evasion by blocking PD-L1 induced by IFN-γ. Mechanistically, some cell cycle-, antiapoptosis-, DNA repair-, metastasis-, and immune evasion-related genes, including BIRC5, XRCC2, CCNB1, CCNE2, PLK1, AURKA, FOXM1, and PD-L1 were identified to be directly regulated by OICR-9429 in a H3K4me3-dependent manner. Conclusions Our novel finding is that the WDR5 inhibitor, OICR-9429, suppressed proliferation, metastasis and PD-L1-based immune evasion while enhancing apoptosis and chemosensitivity to cisplatin in BCa by blocking the WDR5-MLL complex mediating H3K4me3 in target genes. Hence, our findings offer insight into a multipotential anticancer compound, OICR-9429, which enhances the antitumour effect of cisplatin or immunotherapy in BCa.

Soluble programmed death ligand-1(sPD-L1) is elevated in aggressive prostate cancer disease among African men

2021 ◽  
Author(s):  
PAUL KATONGOLE ◽  
Obondo J. Sande ◽  
Steven J Reynolds ◽  
Moses Joloba ◽  
Henry Kajumbula ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Plasma Concentrations ◽  
Enzyme Linked Immunosorbent Assay ◽  
P Value ◽  
Healthy Controls ◽  
Cancer Disease ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
Median Plasma ◽  
Programmed Death 1

Abstract Background The programmed death 1 (PD1)/programmed death-ligand 1 (PDL1) targeted immunotherapies have become a new mode of treatment for several tumours; however, there is limited evidence on the expression and prognostic value of PD1/PDL1 in prostate cancer, especially in African men. Methods The plasma concentrations of PD-L1/PD1 were assessed using Enzyme-Linked Immunosorbent Assay in patients with prostate cancer and normal healthy controls at the Uganda Cancer Institute. The association between plasma PD-L1/PD1 concentration levels and PSA levels, Gleason scores, age, and Body mass index were determined. Results We found significant differences in the median plasma concentrations of PD-L1 and PD-1 immune checkpoint molecules between Prostate cancer cases and normal healthy controls of (0.285 vs 0.035) p-value 0.001 and (0.596 vs 0.355) p-value 0.017, respectively. We found no significant association between age, plasma PSA levels, BMI and Gleason scores, and PD-1 among patients with prostate cancer and controls. However, elevated levels of PD-L1 were significantly associated with raised Gleason scores among patients with prostate cancer with a p-value of <0.001. Conclusions Elevated PD-L1 levels were statistically significantly linked to high Gleason scores. These results may guide clinicians in assessing the prognosis of patients individually and selecting suitable patients that will make favorable candidates for anti-PD-L1 immunotherapy.

scholarly journals E2F and GATA switches turn off WD repeat domain 77 expression in differentiating cells

2016 ◽  
Vol 473 (15) ◽  
pp. 2331-2343 ◽  
Author(s):  
Min Yu ◽  
Ulrica Wang ◽  
Zhengxin Wang
Keyword(s):  
Prostate Cancer ◽  
Lung Cancer ◽  
Lung Development ◽  
Lung Epithelial Cells ◽  
Mouse Lung ◽  
Lung Tumorigenesis ◽  
Repeat Domain ◽  
Gel Shift Assay ◽  
Bona Fide ◽  
Wd Repeat

WDR77 (WD repeat domain 77) is expressed during earlier lung development when cells are rapidly proliferating, but is absent from adult lung. It is re-activated during lung tumorigenesis and is essential for lung cancer cell proliferation. Signalling pathways/molecules that control WDR77 gene expression are unknown. Promoter mapping, gel shift assay and ChIP revealed that the WDR77 promoter contains bona fide response elements for E2F and GATA transcriptional factors as demonstrated in prostate cancer, lung cancer and erythroid cells, as well as in mouse lung tissues. The WDR77 promoter is transactivated by E2F1, E2F3, GATA1 and GATA6, but suppressed by E2F6, GATA1 and GATA3 in prostate cancer PC3 cells. WDR77 expression is associated with E2F1, E2F3, GATA2 and GATA6 occupancy on the WDR77 gene, whereas, in contrast, E2F6, GATA1 and GATA3 occupancy is associated with the loss of WDR77 expression during erythroid maturation and lung development. More importantly, the loss of WDR77 expression that results from E2F and GATA switches is required for cellular differentiation of erythroid and lung epithelial cells. In contrast, lung cancer cells avoid post-mitotic differentiation by sustaining WDR77 expression. Altogether, the present study provides a novel molecular mechanism by which WDR77 is regulated during erythroid and lung development and lung tumorigenesis.

scholarly journals Comprehensive Evaluation of Programmed Death-Ligand 1 Expression in Primary and Metastatic Prostate Cancer

2018 ◽  
Vol 188 (6) ◽  
pp. 1478-1485 ◽  
Author(s):  
Michael C. Haffner ◽  
Gunes Guner ◽  
Diana Taheri ◽  
George J. Netto ◽  
Doreen N. Palsgrove ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Comprehensive Evaluation ◽  
Programmed Death Ligand 1 ◽  
Programmed Death
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