Targeting the DNA-binding activity of the human ERG transcription factor using new heterocyclic dithiophene diamidines

Nhili, Raja; Peixoto, Paul; Depauw, Sabine; Flajollet, Sébastien; Dezitter, Xavier; Munde, Manoj; Ismail, M.; Kumar, Arvind; Farahat, Abdelbasset A.; Stephens, Chad E.; Duterque-Coquillaud, Martine; Wilson, W. David; Boykin, David W.; David-Cordonnier, Marie-Hélène

doi:10.1093/nar/gks971

Cited by 62 publications

(68 citation statements)

References 51 publications

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“…S3B). Among them, according to Nhili and colleagues’ study (34), only two (positions −1050bp and −314 bp) were characterized by strong flanking sequences (black asterisks in Fig. 2A).…”

Section: Resultsmentioning

confidence: 91%

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Suppression of CHK1 by ETS Family Members Promotes DNA Damage Response Bypass and Tumorigenesis

et al. 2015

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The ETS family of transcription factors has been repeatedly implicated in tumorigenesis. In prostate cancer, ETS family members such as ERG, ETV1, ETV4 and ETV5 are frequently overexpressed due to chromosomal translocations, but the molecular mechanisms by which they promote prostate tumorigenesis remain largely undefined. Here we show that ETS family members such as ERG and ETV1 directly repress the expression of the checkpoint kinase 1 (CHK1), a key DNA Damage Response (DDR) cell cycle regulator essential for the maintenance of genome integrity. Critically, we find that ERG expression correlates with CHK1 downregulation in human patients, and demonstrate that Chk1 heterozygosity promotes the progression of high-grade prostatic intraepithelial neoplasia (HGPIN) into prostatic invasive carcinoma (CaP) in Pten+/− mice. Importantly, CHK1 downregulation sensitizes prostate tumor cells to etoposide but not to docetaxel treatment. Thus, we identify CHK1 as a key functional target of the ETS proto-oncogenic family with important therapeutic implications.

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Section: Resultsmentioning

confidence: 91%

“…Asterisks indicate the most probable ERG binding sites according to Nihil and colleagues (34). Purple arrows indicate the two regions of CHK1 promoter identified by Yu and colleagues in a ChIP-seq analysis for ERG (21).…”

Section: Figurementioning

confidence: 99%

Suppression of CHK1 by ETS Family Members Promotes DNA Damage Response Bypass and Tumorigenesis

et al. 2015

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“…The EBD is an 85 amino-acid domain that forms a winged helix-turn-helix motif that binds to DNA sequences that contain a core GGAA/T sequence (18). ERG has been shown to bind to this core sequence (19).…”

Section: Resultsmentioning

confidence: 99%

The oncogenic transcription factor ERG represses the transcription of the tumour suppressor gene PTEN in prostate cancer cells

et al. 2017

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Abstract. The oncogene ETS-related gene (ERG) encodes a transcription factor with roles in the regulation of haematopoiesis, angiogenesis, vasculogenesis, inflammation, migration and invasion. The ERG oncogene is activated in >50% of prostate cancer cases, generally through a gene fusion with the androgen-responsive promoter of transmembrane protease serine 2. Phosphatase and tensin homologue (PTEN) is an important tumour suppressor gene that is often inactivated in cancer. ERG overexpression combined with PTEN inactivation or loss is often associated with aggressive prostate cancer. The present study aimed to determine whether or not ERG regulates PTEN transcription directly. ERG was demonstrated to bind to the PTEN promoter and repress its transcription. ERG overexpression reduced endogenous PTEN expression, whereas ERG knockdown increased PTEN expression. The ability of ERG to repress PTEN may contribute to a more cancer-permissive environment.

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“…Another gene that is being targeted 1215 for cancer therapy is ERG transcription factor, the gene 1216 with the most significant copy number gain in our anal-1217 ysis. Several studies have reported their attempts in de-1218 veloping drugs that target the ERG transcription fac-1219 tor, mostly in prostate cancer [244,245]. Further vali-1220 dation of the results described here would suggest the 1221 expansion of such trials to include melanoma.…”

mentioning

confidence: 78%

Copy number variation in archival melanoma biopsies versus benign melanocytic lesions

Mahas

Potluri

Kent

et al. 2016

CBM

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Abstract. BACKGROUND: Skin melanocytes can give rise to benign and malignant neoplasms. Discrimination of an early melanoma from an unusual/atypical benign nevus can represent a significant challenge. However, previous studies have shown that in contrast to benign nevi, melanoma demonstrates pervasive chromosomal aberrations. OBJECTIVE: This substantial difference between melanoma and benign nevi can be exploited to discriminate between melanoma and benign nevi. METHODS: Array-comparative genomic hybridization (aCGH) is an approach that can be used on DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues to assess the entire genome for the presence of changes in DNA copy number. In this study, high resolution, genome-wide single-nucleotide polymorphism (SNP) arrays were utilized to perform comprehensive and detailed analyses of recurrent copy number aberrations in 41 melanoma samples in comparison with 21 benign nevi. RESULTS: We found statistically significant copy number gains and losses within melanoma samples. Some of the identified aberrations are previously implicated in melanoma. Moreover, novel regions of copy number alterations were identified, revealing new candidate genes potentially involved in melanoma pathogenesis. CONCLUSIONS: Taken together, these findings can help improve melanoma diagnosis and introduce novel melanoma therapeutic targets.Keywords: Array comparative genomic hybridization, melanoma, FFPE highly lethal forms of cancer. Although it accounts 10 for the minority of skin cancers, a large majority 11 (75%) of skin cancer related-deaths are accounted for 12 by melanoma [1,2]. The incidence and mortality of 13 melanoma has increased dramatically in the last few 14 decades [3]. The American Cancer Society estimates 15 that about 73,870 people in United States will be diag-16 nosed with melanoma in 2015 and about 9,940 people 17 are expected to die from the disease. Importantly, the 18 5-year survival rate of melanoma depends on the stage 19 of the disease when it is diagnosed. It can be as high 20 as 98% when the melanoma is detected early before 21 it spreads to the lymph nodes or other organs. When 22 melanoma reaches the lymph nodes, the 5-year sur-23 vival rate drops to 62%, and to 15% when melanoma 24 spread to other organs [2]. Sequences for the primer pairs and cycling parame-286 ters were as follows: 5'-AATCGGGCTG-3' and 5'-287 GAAACGGGTG-3', 94• C for 2.5 minutes, then 45 cy-288 cles of 1 minute 94• C, 1 minute 55 • C and 2 minutes 289 72• C, then 7 minutes 72 • C and holding at 4 • C; or 5 -290 TGTGCCCAGTGAAGACTCAG-3' and 5 -GAGTGA 291 GCGGAGAGGGAACT-3', 45 cycles of 94• C for 1 292 minute, 35• C for 1 minute, and 72• C for 2 minute. 293 PCR products were resolved on 3% TBE agarose plus 294 SYBR Safe dye (Life Technologies). Gels were visu-295 alized with a GE ImageQuant LAS-3000 camera (GE 296 Healthcare Life Sciences, Piscataway, NJ, USA). Microarrays 298DNA copy number analysis was performed by hy-299 bridizing the extracted and qualified gDNA to Affy-300 metrix...

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Targeting the DNA-binding activity of the human ERG transcription factor using new heterocyclic dithiophene diamidines

Cited by 62 publications

References 51 publications

Suppression of CHK1 by ETS Family Members Promotes DNA Damage Response Bypass and Tumorigenesis

Suppression of CHK1 by ETS Family Members Promotes DNA Damage Response Bypass and Tumorigenesis

The oncogenic transcription factor ERG represses the transcription of the tumour suppressor gene PTEN in prostate cancer cells

Copy number variation in archival melanoma biopsies versus benign melanocytic lesions

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