Inhibition of GATA2 in prostate cancer by a clinically available small molecule

Kaochar, Salma; Rusin, Aleksandra; Foley, Christopher; Rajapakshe, Kimal; Robertson, Matthew J.; Skapura, Darlene G.; Mason, Cammy; Ruiz, Karen Berman de; Tyryshkin, Alexey; Deng, Jenny; Shin, Jin Na; Fiskus, Warren; Dong, Jianrong; Huang, Shixia; Navone, Nora M.; Davis, Christel M.; Ehli, Erik A.; Coarfa, Cristian; Mitsiades, Nicholas

doi:10.1530/erc-21-0085

Cited by 11 publications

(5 citation statements)

References 70 publications

(138 reference statements)

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“…3; Supplementary Data9). Similarly, we also highlighted key TFs, NKX3-1 (66-69) and GATA2 (70)(71)(72)(73) for prostate cancer (Supplementary Data10).…”

Section: Discussionmentioning

confidence: 86%

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Enhancing Disease Risk Gene Discovery by Integrating Transcription Factor-Linked Trans-located Variants into Transcriptome-Wide Association Analyses

He,

Perera,

Wen

et al. 2023

Preprint

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Transcriptome-wide association studies (TWAS) have been successful in identifying putative disease susceptibility genes by integrating gene expression predictions with genome-wide association studies (GWAS) data. However, current TWAS models only consider cis-located variants to predict gene expression. Here, we introduce transTF-TWAS, which includes transcription factor (TF)-linked trans-located variants for model building. Using data from the Genotype-Tissue Expression project, we predict alternative splicing and gene expression and applied these models to large GWAS datasets for breast, prostate, and lung cancers. Our analysis revealed 887 putative cancer susceptibility genes, including 465 in regions not yet reported by previous GWAS and 137 in known GWAS loci but not yet reported previously, at Bonferroni-corrected P < 0.05. We demonstrate that transTF-TWAS surpasses other approaches in both building gene prediction models and identifying disease-associated genes. These results have shed new light on several genetically driven key regulators and their associated regulatory networks underlying disease susceptibility.

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“…3; Supplementary Data9). Similarly, we also highlighted key TFs, NKX3-1 (66-69) and GATA2 (70)(71)(72)(73) for prostate cancer (Supplementary Data10).…”

Section: Discussionmentioning

confidence: 86%

“…3; Table S9). Similarly, we also highlighted key TFs, NKX3-1 [62][63][64][65] and GATA2 [66][67][68][69] for prostate cancer (Table S10). Unfortunately, we did not observe significant TFs in lung cancer, likely due to the less genetic effects of the TF on downstream regulated genes 38 .…”

Section: Discussionmentioning

confidence: 87%

Enhancing Disease Risk Gene Discovery by Integrating Transcription Factor-Linked Trans-located Variants into Transcriptome-Wide Association Analyses

He,

Perera,

Wen

et al. 2023

Preprint

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“…GATA2 could promote PCa progression in an AR-dependent manner, embodied in facilitating the expression of AR and AR target gene, which was also considered to function as a pioneer factor [ 51 , 52 ]. In addition, GATA2 was involved in the development of CRPC and metastatic PCa [ 53 ] through directly upregulating a battery of target genes, such as BMP6, EZH2, FOXM1 and IGF2, which were associated with PCa metastasis and taxane resistance [ 26 , 54 , 55 ]. Our current study indicated that ST6GALNAC5 may also contribute to the oncogenic effects of GATA2 to promote PCa cell invasion.…”

Section: Discussionmentioning

confidence: 99%

Integrative analysis of the ST6GALNAC family identifies GATA2-upregulated ST6GALNAC5 as an adverse prognostic biomarker promoting prostate cancer cell invasion

Zhang

et al. 2023

Cancer Cell Int

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Background ST6GALNAC family members function as sialyltransferases and have been implicated in cancer progression. However, their aberrant expression levels, prognostic values and specific roles in metastatic prostate cancer (PCa) remain largely unclear. Methods Two independent public datasets (TCGA-PRAD and GSE21032), containing 648 PCa samples in total, were employed to comprehensively examine the mRNA expression changes of ST6GALNAC family members in PCa, as well as their associations with clinicopathological parameters and prognosis. The dysregulation of ST6GALNAC5 was further validated in a mouse PCa model and human PCa samples from our cohort (n = 64) by immunohistochemistry (IHC). Gene Set Enrichment Analysis, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and drug sensitivity analyses were performed to enrich the biological processes most related to ST6GALNAC5. Sulforhodamine B, transwell, luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to examine the PCa cell proliferation, invasion and transcriptional regulation, respectively. Results Systematical investigation of six ST6GALNAC family members in public datasets revealed that ST6GALNAC5 was the only gene consistently and significantly upregulated in metastatic PCa, and ST6GALNAC5 overexpression was also positively associated with Gleason score and predicted poor prognosis in PCa patients. IHC results showed that (1) ST6GALNAC5 protein expression was increased in prostatic intraepithelial neoplasia and further elevated in PCa from a PbCre;PtenF/F mouse model; (2) overexpressed ST6GALNAC5 protein was confirmed in human PCa samples comparing with benign prostatic hyperplasia samples from our cohort (p < 0.001); (3) ST6GALNAC5 overexpression was significantly correlated with perineural invasion of PCa. Moreover, we first found transcription factor GATA2 positively and directly regulated ST6GALNAC5 expression at transcriptional level. ST6GALNAC5 overexpression could partially reverse GATA2-depletion-induced inhibition of PCa cell invasion. The GATA2-ST6GALNAC5 signature exhibited better prediction on the poor prognosis in PCa patients than GATA2 or ST6GALNAC5 alone. Conclusions Our results indicated that GATA2-upregulated ST6GALNAC5 might serve as an adverse prognostic biomarker promoting prostate cancer cell invasion.

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“…K7174 also significantly reduces tumor growth in a murine xenograft model of CRPC (48). Dilazep, a vasodilator that is used to treat patients with hypertension, cardiovascular, and renovascular disorders, is a second pharmaceutical agent that blocks GATA2 DNA-binding, suppresses the expression of AR, and reduces tumor growth in a murine xenograft model of CRPC (50). These therapeutic options have not yet been tested clinically for men with prostate cancer, however.…”

Section: Gata2 and The Armentioning

confidence: 99%

To bind or not to bind: Cistromic reprogramming in prostate cancer

et al. 2022

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The term “cistrome” refers to the genome-wide location of regulatory elements associated with transcription factor binding-sites. The cistrome of key regulatory factors in prostate cancer etiology are substantially reprogrammed and altered during prostatic transformation and disease progression. For instance, the cistrome of the androgen receptor (AR), a ligand-inducible transcription factor central in normal prostate epithelium biology, is directly impacted and substantially reprogrammed during malignant transformation. Accumulating evidence demonstrates that additional transcription factors that are frequently mutated, or aberrantly expressed in prostate cancer, such as the pioneer transcription factors Forkhead Box A1 (FOXA1), the homeobox protein HOXB13, and the GATA binding protein 2 (GATA2), and the ETS-related gene (ERG), and the MYC proto-oncogene, contribute to the reprogramming of the AR cistrome. In addition, recent findings have highlighted key roles for the SWI/SNF complex and the chromatin-modifying helicase CHD1 in remodeling the epigenome and altering the AR cistrome during disease progression. In this review, we will cover the role of cistromic reprogramming in prostate cancer initiation and progression. Specifically, we will discuss the impact of key prostate cancer regulators, as well as the role of epigenetic and chromatin regulators in relation to the AR cistrome and the transformation of normal prostate epithelium. Given the importance of chromatin-transcription factor dynamics in normal cellular differentiation and cancer, an in-depth assessment of the factors involved in producing these altered cistromes is of great relevance and provides insight into new therapeutic strategies for prostate cancer.

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Inhibition of GATA2 in prostate cancer by a clinically available small molecule

Cited by 11 publications

References 70 publications

Enhancing Disease Risk Gene Discovery by Integrating Transcription Factor-Linked Trans-located Variants into Transcriptome-Wide Association Analyses

Enhancing Disease Risk Gene Discovery by Integrating Transcription Factor-Linked Trans-located Variants into Transcriptome-Wide Association Analyses

Integrative analysis of the ST6GALNAC family identifies GATA2-upregulated ST6GALNAC5 as an adverse prognostic biomarker promoting prostate cancer cell invasion

To bind or not to bind: Cistromic reprogramming in prostate cancer

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