Suppression of <i>CHK1</i> by ETS Family Members Promotes DNA Damage Response Bypass and Tumorigenesis

Lunardi, Andrea; Varmeh, Shohreh; Chen, Ming; Taulli, Riccardo; Guarnerio, Jlenia; Ala, Ugo; Seitzer, Nina; Ishikawa, T.; Carver, Brett S.; Hobbs, Robin M.; Quarantotti, Valentina; Ng, Christopher; Berger, Alice H.; Nardella, Caterina; Poliseno, Laura; Montironi, Rodolfo; Castillo-Martín, Mireia; Cordon‐Cardo, Carlos; Signoretti, Sabina; Pandolfi, Pier Paolo

doi:10.1158/2159-8290.cd-13-1050

Cited by 27 publications

(29 citation statements)

References 66 publications

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“…Consistent with the previous reports, 21, 22 we observed a relatively high basal level of γ -H2Ax foci and spontaneous apoptosis in VCaP cells, reflecting DNA damage caused by ERG upregulation. Notably, at 50 nM, MLN slightly decreased the incidence of γ -H2AX foci, implying that the G0/G1 cell cycle arrest and reduced rate of DNA synthesis induced at this dose prevented spontaneous DNA breaks.…”

Section: Resultssupporting

confidence: 93%

Distinct outcomes of CRL–Nedd8 pathway inhibition reveal cancer cell plasticity

et al. 2016

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Inhibition of protein degradation by blocking Cullin-RING E3 ligases (CRLs) is a new approach in cancer therapy though of unknown risk because CRL inhibition may stabilize both oncoproteins and tumor suppressors. Probing CRLs in prostate cancer cells revealed a remarkable plasticity of cells with TMPRSS2-ERG translocation. CRL suppression by chemical inhibition or knockdown of RING component RBX1 led to reversible G0/G1 cell cycle arrest that prevented cell apoptosis. Conversely, complete blocking of CRLs at a higher inhibitor dose-induced cytotoxicity that was amplified by knockdown of CRL regulator Cand1. We analyzed cell signaling to understand how varying degrees of CRL inhibition translated to distinct cell fates. Both tumor suppressor and oncogenic cell signaling pathways and transcriptional activities were affected, with pro-metastatic Wnt/β-catenin as the most upregulated. Suppression of the NF-κB pathway contributed to anti-apoptotic effect, and androgen receptor (AR) and ERG played decisive, though opposite, roles: AR was involved in protective quiescence, whereas ERG promoted apoptosis. These data define AR–ERG interaction as a key plasticity and survival determinant in prostate cancer and suggest supplementary treatments that may overcome drug resistance mechanisms regulated by AR–ERG interaction.

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Section: Resultssupporting

confidence: 93%

Distinct outcomes of CRL–Nedd8 pathway inhibition reveal cancer cell plasticity

et al. 2016

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“…The proportion of cells in S-phase at 24 h following the IR and PARPi combination treatment was 2-fold greater in TMPRSS2-ERG compared to parental PC3 cells. These data could partially explain the increased radiosensitivity of TMPRSS2-ERG-positive cells with PARPi treatment (13), as cell cycle arrest due to checkpoint activation after IR was reduced in the presence of TMPRSS2-ERG compared to PC3 parental cells, as recently reported (33), yet PARP inhibition compensated for this reduction.…”

Section: Resultssupporting

confidence: 60%

“…A recent report has shown that ERG directly represses the expression of the checkpoint kinase 1 (CHK1), a key DNA damage response cell cycle regulator that is essential for the maintenance of genome integrity. This study found that ERG expression correlates with CHK1 downregulation in human patients and that CHK1 downregulation sensitized PCa cells to DNA-damage (etoposide) but not docetaxel-based treatment (33). This finding provides support for the cell cycle differences we observed in the TMPRSS2-ERG-expressing cells.…”

Section: Discussionmentioning

confidence: 76%

The TMPRSS2–ERG Gene Fusion Blocks XRCC4-Mediated Nonhomologous End-Joining Repair and Radiosensitizes Prostate Cancer Cells to PARP Inhibition

Chatterjee

Choudhary

Alswillah

et al. 2015

Molecular Cancer Therapeutics

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Exposure to genotoxic agents, such as ionizing radiation (IR) produces DNA damage leading to DNA double-strand breaks (DSBs); IR toxicity is augmented when the DNA repair is impaired. We reported that radiosensitization by a PARP inhibitor (PARPi) was highly prominent in prostate cancer (PCa) cells expressing the TMPRSS2-ERG gene fusion protein. Here, we show that TMPRSS2-ERG blocks non-homologous end-joining (NHEJ) DNA repair by inhibiting DNA-PKcs. VCaP cells, which harbor TMPRSS2-ERG and PC3 cells that stably express it displayed γH2AX and 53BP1 foci constitutively, indicating persistent DNA damage that was absent if TMPRSS2-ERG was depleted by siRNA in VCaP cells. The extent of DNA damage was enhanced and associated with TMPRSS2-ERG’s ability to inhibit DNA-PKcs function, as indicated by its own phosphorylation (Thr2609, Ser2056) and that of its substrate, Ser1778-53BP1. DNA-PKcs deficiency caused by TMPRSS2-ERG destabilized critical NHEJ components on chromatin. Thus, XRCC4 was not recruited to chromatin, with retention of other NHEJ core factors being reduced. DNA-PKcs autophosphorylation was restored to the level of parental cells when TMPRSS2-ERG was depleted by siRNA. Following IR, TMPRSS2-ERG-expressing PC3 cells had elevated Rad51 foci and homologous recombination (HR) activity, indicating that HR compensated for defective NHEJ in these cells, hence addressing why TMPRSS2-ERG alone did not lead to radiosensitization. However, the presence of TMPRSS2-ERG, by inhibiting NHEJ DNA repair, enhanced PARPi-mediated radiosensitization. IR in combination with PARPi resulted in enhanced DNA damage in TMPRSS2-ERG-expressing cells. Thus, by inhibiting NHEJ, TMPRSS2-ERG provides a synthetic lethal interaction with PARPi in PCa patients expressing TMPRSS2-ERG.

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“…Even more strikingly, the genes of several key signaling factors (PAK1, CREM) and of the epigenetic modulator SMARCD3 have apparently acquired ERG binding capability in their promoter regions during tumorigenesis (for SMARCC1, see Extended Data Fig. 4c), as it was reported for the ERG-mediated repression of checkpoint kinase 1 31 . In contrast, P6 showed a very small number of deregulated components of the core Wnt pathway (Fig.…”

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confidence: 63%

Patient-matched analysis identifies deregulated networks in prostate cancer to guide personalized therapeutic intervention

Kumar

Kasikçi

Badredine

et al. 2019

Preprint

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Prostate cancer (PrCa) is the second most common malignancy in men 1 . More than 50% of advanced prostate cancers display the TMPRSS2-ERG fusion 2 . Despite extensive cancer genome/transcriptome 2-4 and phosphoproteome 5 data, little is known about the impact of mutations and altered transcription on regulatory networks in the PrCa of individual patients.Using patient-matched normal and tumor samples, we established somatic variations and differential transcriptome profiles of primary ERG-positive prostate cancers. Integration of protein-protein interaction and gene-regulatory network databases 6,7 defined highly diverse patient-specific network alterations. We found that different components of a given regulatory pathway were altered by novel and known mutations and/or aberrant gene expression, including deregulated ERG targets, such that different sets of pathways were altered in each individual PrCa. In a given PrCa, several deregulated pathways share common factors, predicting synergistic effects on cancer progression. Our integrated analysis provides a paradigm to identify key deregulated factors within regulatory networks to guide personalized therapies.The mutational landscapes of primary and advanced/metastatic PrCa have been extensively analyzed 2,3,8,9 , as has been the prevalence of the androgen-sensitive TMPRSS2 promoter fusion with ETS transcription factors 10 , which endows ETS with responsiveness to the androgen receptor (AR) that is frequently overexpressed in antiandrogen-resistant PrCa 11 . Recurrent mutations have been found in genes coding for factors regulating a plethora of pathways and key cellular functions, such as the androgen receptor signaling, PI3K/RAS/RAF/WNT pathways, Extended Data Fig. 5: Patient-specific deregulations of the PDGF and EGFR pathway components for the indicated patients (P). a, Merged network of 10 patients used a background in (b) to (l) for PDGF pathway. j, Merged network of 7 patients used as a background in (k) to (o) for EGFR pathway. Frame and color codes are shown below P12. b to i, deregulated and/or mutated components of the PDGF pathway in each patient. k to o deregulated and/or mutated components of EGFR pathway in each patient. Extended Data Fig. 6: Patient-specific deregulations of the PDGF and EGFR pathway components for the indicated patients (P). a, Network display of deregulated and mutated factors of patient P1 in the WNT, Angiogenesis and Cytokine Pathways to reveal connectivities between the different pathways. b, Similar representation of the de-regulated and mutated factors in P2 for the WNT, PDGF and EGFR pathways.

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

Cited by 27 publications

References 66 publications

Distinct outcomes of CRL–Nedd8 pathway inhibition reveal cancer cell plasticity

Distinct outcomes of CRL–Nedd8 pathway inhibition reveal cancer cell plasticity

The TMPRSS2–ERG Gene Fusion Blocks XRCC4-Mediated Nonhomologous End-Joining Repair and Radiosensitizes Prostate Cancer Cells to PARP Inhibition

Patient-matched analysis identifies deregulated networks in prostate cancer to guide personalized therapeutic intervention

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