GATA2 as a potential metastasis-driving gene in prostate cancer

Chiang, Yan Ting; Wang, Kendric; Fazli, Ladan; Qi, Robert Z.; Gleave, Martin; Collins, Colin C.; Gout, Peter W.; Wang, Yuzhuo

doi:10.18632/oncotarget.1296

Cited by 57 publications

(48 citation statements)

References 49 publications

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“…GATA2 is a factor normally involved in hematopoiesis and mutations in GATA2 are seen in myelodysplastic syndrome, acute myeloid leukemia, and chronic myeloid leukemia (Crispino and Horwitz, 2017). However, GATA2 is also associated with prostate cancer (Chiang et al, 2014; Crispino and Horwitz, 2017; He et al, 2014; Xiao et al, 2016). GATA2 is considered to be a pioneer transcription factor that facilitates coactivator recruitment to the androgen receptor transcription complex to regulate a key set of genes related to prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

A Prostate Cancer Risk Element Functions as a Repressive Loop that Regulates HOXA13

et al. 2017

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Summary Prostate cancer (PCa) is the leading cancer among men in the United States, with genetic factors contributing to ~42% of the susceptibility to PCa. We analyzed a PCa risk region located at 7p15.2 to gain insight into the mechanisms by which this noncoding region may affect gene regulation and contribute to PCa risk. We performed Hi-C analysis and demonstrated that this region has long range interactions with the HOXA locus, located ~873 kb away. Using the CRISPR/Cas9 system, we deleted a 4kb region encompassing several prostate cancer risk-associated SNPs and performed RNA-seq to investigate transcriptomic changes in prostate cells lacking the regulatory element. Our results suggest that the risk element affects the expression of HOXA13 and HOTTIP, but not other genes in the HOXA locus, via a repressive loop. Forced expression of HOXA13 was performed to gain further insight into the mechanisms by which this risk element affects PCa risk.

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Section: Discussionmentioning

confidence: 99%

A Prostate Cancer Risk Element Functions as a Repressive Loop that Regulates HOXA13

et al. 2017

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“…Tissue microarrays (TMA) were manually constructed, as previously described (37,38), using various Gleason grades-exhibiting prostate cancer specimens (n ¼ 342), obtained from the Vancouver Prostate Centre Tissue Bank with written informed consent of patients, clinical information, and institutional study approval. All specimens were obtained through radical prostatectomy, except CRPC samples that were obtained via transurethral resection of the prostate.…”

Section: Human Prostate Cancer Tma Construction and Ihcmentioning

confidence: 99%

“…The migration and invasion potential of PC-3 cells following treatment with MCT4 ASOs was investigated using Matrigelcoated modified Boyden chambers (BD Biosciences) as previously described (38). Briefly, ASO-treated cells were seeded into the top chamber at 50,000 live cells per well.…”

Section: Modified Boyden Chamber Assaymentioning

confidence: 99%

TheMCT4Gene: A Novel, Potential Target for Therapy of Advanced Prostate Cancer

Choi

Xue

et al. 2016

Clinical Cancer Research

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Purpose: The management of castration-resistant prostate cancer (CRPC) is a major challenge in the clinic. Androgen receptor signaling–directed strategies are not curative in CRPC therapy, and new strategies targeting alternative, key cancer properties are needed. Using reprogrammed glucose metabolism (aerobic glycolysis), cancer cells typically secrete excessive amounts of lactic acid into their microenvironment, promoting cancer development, survival, and progression. Cellular lactic acid secretion is thought to be predominantly mediated by MCT4, a plasma membrane transporter protein. As such, the MCT4 gene provides a unique, potential therapeutic target for cancer. Experimental Design: A tissue microarray of various Gleason grade human prostate cancers was stained for MCT4 protein. Specific, MCT4-targeting antisense oligonucleotides (MCT4 ASO) were designed and candidate MCT4 ASOs checked for effects on (i) MCT4 expression, lactic acid secretion/content, glucose consumption, glycolytic gene expression, and proliferation of human CRPC cells and (ii) growth of PC-3 tumors in nude mice. Results: Elevated MCT4 expression was associated with human CRPC and an earlier time to relapse. The treatment of PC-3, DU145, and C4-2 CRPC cultures with candidate MCT4 ASOs led to marked inhibition of MCT4 expression, lactic acid secretion, to increased intracellular lactic acid levels, and markedly reduced aerobic glycolysis and cell proliferation. Treatment of PC-3 tumor-bearing nude mice with the MCT4 ASOs markedly inhibited tumor growth without inducing major host toxicity. Conclusions: MCT4-targeting ASOs that inhibit lactic acid secretion may be useful for therapy of CRPC and other cancers, as they can interfere with reprogrammed energy metabolism of cancers, an emerging hallmark of cancer. Clin Cancer Res; 22(11); 2721–33. ©2016 AACR.

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“…ChIP-on-chip analysis revealed that the GATAbinding motif is enriched in the AR-binding chromatin regions in LNCaP cells (23). GATA2 has been reported to facilitate androgen-responsive gene expression (24) and to promote cell migration, tissue invasion, and metastasis (25). It has been reported that GATA2 can directly regulate AR gene expression in a stable LNCaP cell line with doxycycline-inducible GATA2 (26).…”

Section: Significancementioning

confidence: 99%

GATA2 facilitates steroid receptor coactivator recruitment to the androgen receptor complex

Lanz

Fiskus

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

107

159

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The androgen receptor (AR) is a key driver of prostate cancer (PC), even in the state of castration-resistant PC (CRPC) and frequently even after treatment with second-line hormonal therapies such as abiraterone and enzalutamide. The persistence of AR activity via both ligand-dependent and ligand-independent mechanisms (including constitutively active AR splice variants) highlights the unmet need for alternative approaches to block AR signaling in CRPC. We investigated the transcription factor GATA-binding protein 2 (GATA2) as a regulator of AR signaling and an actionable therapeutic target in PC. We demonstrate that GATA2 directly promotes expression of both full-length and splice-variant AR, resulting in a strong positive correlation between GATA2 and AR expression in both PC cell lines and patient specimens. Conversely, GATA2 expression is repressed by androgen and AR, suggesting a negative feedback regulatory loop that, upon androgen deprivation, derepresses GATA2 to contribute to AR overexpression in CRPC. Simultaneously, GATA2 is necessary for optimal transcriptional activity of both fulllength and splice-variant AR. GATA2 colocalizes with AR and Forkhead box protein A1 on chromatin to enhance recruitment of steroid receptor coactivators and formation of the transcriptional holocomplex. In agreement with these important functions, high GATA2 expression and transcriptional activity predicted worse clinical outcome in PC patients. A GATA2 small molecule inhibitor suppressed the expression and transcriptional function of both full-length and splice-variant AR and exerted potent anticancer activity against PC cell lines. We propose pharmacological inhibition of GATA2 as a firstin-field approach to target AR expression and function and improve outcomes in CRPC.prostate cancer | small molecule inhibitor | AR signaling | GATA2 | steroid receptor coactivator

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GATA2 as a potential metastasis-driving gene in prostate cancer

Cited by 57 publications

References 49 publications

A Prostate Cancer Risk Element Functions as a Repressive Loop that Regulates HOXA13

A Prostate Cancer Risk Element Functions as a Repressive Loop that Regulates HOXA13

TheMCT4Gene: A Novel, Potential Target for Therapy of Advanced Prostate Cancer

GATA2 facilitates steroid receptor coactivator recruitment to the androgen receptor complex

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