SPOP mutation confers intrinsic BET inhibitor resistance in prostate cancer
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PROVIDER: PRJNA348842 | ENA |
REPOSITORIES: ENA
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Project description:Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising therapeutics of cancers including prostate cancer. The E3 ubiquitin ligase adaptor protein speckle-type POZ protein (SPOP) is implicated in human prostate cancers due to its frequent mutation. Here we demonstrate that SPOP binds to the BET proteins BRD2, BRD3 and BRD4. Wild-type SPOP, but not prostate cancer-associated mutants, promotes polyubiquitination and proteasome degradation of BET proteins by recognizing a common degron motif. BET protein levels are highly elevated in SPOP-mutated prostate cancers in patients. Expression of cancer-derived SPOP mutants upregulates cholesterol biosynthesis genes and confers resistance to the BET inhibitor in cultured prostate cancer cells and tumors in mice, and this effect can be overcome by the AKT inhibitor. Our findings reveal BET proteins as proteolytic targets of SPOP and identify deregulated cholesterol biosynthesis as a downstream event of SPOP mutation-mediated tumorigenesis and therapy resistance in prostate cancer.
2018-03-08 | GSE98010 | GEO
Project description:Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising therapeutics of cancers including prostate cancer. The E3 ubiquitin ligase adaptor protein speckle-type POZ protein (SPOP) is implicated in human prostate cancers due to its frequent mutation. Here we demonstrate that SPOP binds to the BET proteins BRD2, BRD3 and BRD4. Wild-type SPOP, but not prostate cancer-associated mutants, promotes polyubiquitination and proteasome degradation of BET proteins by recognizing a common degron motif. BET protein levels are highly elevated in SPOP-mutated prostate cancers in patients. Expression of cancer-derived SPOP mutants upregulates cholesterol biosynthesis genes and confers resistance to the BET inhibitor in cultured prostate cancer cells and tumors in mice, and this effect can be overcome by the AKT inhibitor. Our findings reveal BET proteins as proteolytic targets of SPOP and identify deregulated cholesterol biosynthesis as a downstream event of SPOP mutation-mediated tumorigenesis and therapy resistance in prostate cancer.
2017-07-24 | GSE88871 | GEO
Project description:Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising therapeutics of cancers including prostate cancer. The E3 ubiquitin ligase adaptor protein speckle-type POZ protein (SPOP) is implicated in human prostate cancers due to its frequent mutation. Here we demonstrate that SPOP binds to the BET proteins BRD2, BRD3 and BRD4. Wild-type SPOP, but not prostate cancer-associated mutants, promotes polyubiquitination and proteasome degradation of BET proteins by recognizing a common degron motif. BET protein levels are highly elevated in SPOP-mutated prostate cancers in patients. Expression of cancer-derived SPOP mutants upregulates cholesterol biosynthesis genes and confers resistance to the BET inhibitor in cultured prostate cancer cells and tumors in mice, and this effect can be overcome by the AKT inhibitor. Our findings reveal BET proteins as proteolytic targets of SPOP and identify deregulated cholesterol biosynthesis as a downstream event of SPOP mutation-mediated tumorigenesis and therapy resistance in prostate cancer.
2017-07-24 | GSE78213 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-07-21 | GSE88872 | GEO
Project description:Janouskova H, El Tekle G, Bellini E, Udeshi ND, Rinaldi A, Ulbricht A, Bernasocchi T, Civenni G, Losa M, Svinkina T, Bielski CM, Kryukov GV, Cascione L, Sara Napoli S, Enchev RI, Mutch DG, Carney ME, Berchuck A, Winterhoff BJN, Broaddus RR, Schraml P, Moch H, Bertoni F, Catapano CV, Peter M, Carr SA, Garraway LA, Wild PJ, and Theurillat JP. Nature Medicine 2017.
It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer-associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially degraded by endometrial cancer-associated SPOP mutants. The resulting reduction of BET protein levels sensitized cancer cells to BET inhibitors. Conversely, prostate cancer-specific SPOP mutations resulted in impaired degradation of BETs, promoting their resistance to pharmacologic inhibition.These results uncover an oncogenomics paradox, whereby mutations mapping to the same domain evoke opposing drug susceptibilities. Specifically, we provide a molecular rationale for the use of BET inhibitors to treat patients with endometrial but not prostate cancer who harbor SPOP mutations.
2016-12-16 | MSV000080401 | MassIVE
Project description:Recurrent point mutations in SPOP define a distinct molecular subclass of prostate cancer. Here, we describe the first mouse model showing that mutant SPOP drives prostate tumorigenesis in vivo. Conditional expression of mutant SPOP in the prostate dramatically altered phenotypes in the setting of Pten loss, with early neoplastic lesions (high-grade prostatic intraepithelial neoplasia) with striking nuclear atypia, and invasive poorly differentiated carcinoma. In mouse prostate organoids, mutant SPOP drove increased proliferation and a transcriptional signature consistent with human prostate cancer. Using these models and human prostate cancer samples, we show that SPOP mutation activates both PI3K/mTOR and androgen receptor (AR) signaling, effectively uncoupling the normal negative feedback between these two pathways. Associated RNA-seq data deposited in GEO: GSE94839.
2017-03-20 | PXD005309 | Pride
Project description:We aimed at analyzing the transcriptome changes associated with SPOP mutation in DU145 cells
2020-07-15 | GSE147090 | GEO
Project description: Not available
| S-EPMC5653288 | biostudies-literature
Project description:Bromodomain and Extra Terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic paradigm by directly targeting epigenetic readers. Early clinical trials have shown significant promise especially in acute myeloid leukaemia (AML)3; therefore the evaluation of resistance mechanisms, an inevitable consequence of cancer therapies, is of utmost importance to optimise the clinical efficacy of these drugs. Using primary murine stem and progenitor cells immortalised with MLL-AF9, we have used an innovative approach to generate 20 cell lines derived from single cell clones demonstrating stable resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is not mediated through increased drug efflux or metabolism but is demonstrated to emerge from leukaemia stem cells (LSC). Resistant clones display a leukaemic granulocyte-macrophage progenitor (L-GMP) phenotype (Lin-, Sca-, cKit+, CD34+, FcγRII/RIII+) and functionally exhibit increased clonogenic capacity in vitro and markedly shorter leukaemia latency in vivo. Chromatin bound BRD4 is globally reduced in resistant cells, however expression of key target genes such as MYC remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors is in part a consequence of increased Wnt/β-catenin signaling. Negative regulation of this pathway results in differentiation of resistant cells into mature leukaemic blasts, inhibition of MYC expression and restoration of sensitivity to I-BET in vitro and in vivo. Finally, we show that the sensitivity of primary human AML cells to I-BET correlates with the baseline expression of Wnt/β-catenin target genes. Together these findings provide novel insights into the biology of AML, highlight the potential therapeutic limitations of BET inhibitors and identify strategies that may overcome resistance and enhance the clinical utility of these unique targeted therapies. Total RNA obtained from iBET resistant and sensitive cells
2015-09-15 | E-GEOD-63575 | biostudies-arrayexpress
Project description:SPOP mutation confers intrinsic BET inhibitor resistance in prostate cancer (BRD4_JQ1_RNA-seq)
| PRJNA312942 | ENA