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

ABSTRACT: 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.

SUBMITTER: Yu M

PROVIDER: S-EPMC5294919 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Yu Min M Wang Ulrica U Wang Zhengxin Z

The Biochemical journal 20160607 15

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 ...[more]

PMID: 27274086

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Project description:BackgroundChemotherapy 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.MethodsWe 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.ResultsFirst, 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.ConclusionsOur 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.

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

Publications

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

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