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Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer (RNA-Seq)

ABSTRACT: Constitutively active androgen receptor (AR) signaling confers resistance to AR-targeted therapies. Here we show that the ubiquitin-mediated proteolysis pathway plays a critical role in the degradation of AR and its variants, particularly variant 7 (AR-V7). AR/AR-V7 proteinhomeostasis (proteostasis) requires interaction of the E3 ubiquitin ligase STUB1 and HSP70complex. STUB1 disassociates AR/AR-V7 from HSP70, leading to AR/AR-V7 ubiquitination and degradation. Inhibition of HSP70 reduces AR/AR-V7 expression which significantly inhibits prostate tumor growth and improves enzalutamide/abiraterone treatments. Clinically, HSP70 expression is upregulated and correlated with AR/AR-V7 levels in high Gleason scores prostate tumors. Our results reveal a novel mechanism of AR-V7 modulation via proteostasis which could be targeted to reduce AR-V7 expression and overcome resistance to AR-targeted therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE120004 | GEO | 2018/10/05

REPOSITORIES: GEO

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Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer (Affymetrix)

Project description:Constitutively active androgen receptor (AR) signaling confers resistance to AR-targeted therapies. Here we show that the ubiquitin-mediated proteolysis pathway plays a critical role in the degradation of AR and its variants, particularly variant 7 (AR-V7). AR/AR-V7 proteinhomeostasis (proteostasis) requires interaction of the E3 ubiquitin ligase STUB1 and HSP70complex. STUB1 disassociates AR/AR-V7 from HSP70, leading to AR/AR-V7 ubiquitination and degradation. Inhibition of HSP70 reduces AR/AR-V7 expression which significantly inhibits prostate tumor growth and improves enzalutamide/abiraterone treatments. Clinically, HSP70 expression is upregulated and correlated with AR/AR-V7 levels in high Gleason scores prostate tumors. Our results reveal a novel mechanism of AR-V7 modulation via proteostasis which could be targeted to reduce AR-V7 expression and overcome resistance to AR-targeted therapies.

2018-10-05 | GSE120005 | GEO

Proteostasis perturbation of N-Myc by HSP70 inhibition improves treatment in neuroendocrine prostate cancer II

Project description:N-Myc is a key driver of neuroendocrine tumors, such as neuroblastoma and neuroendocrine prostate cancer (NEPC). However, N-Myc is considered undruggable because it lacks clear binding sites for small molecules. One potential way to circumvent this challenge is to identify and target the protein homeostasis (proteostasis) system(s) that maintain N-Myc levels. Here we developed a novel spontaneously indefinite prostate cancer cell line UCDCaP and its paired castration-resistant line UCDCaP-CR, which exhibits neural lineage plasticity and high levels of N-Myc protein expression. Through rapid immunoprecipitation mass spectrometry assay, we revealed that heat shock protein 70 (HSP70) is a top partner for N-Myc. HSP70 is known to function in protein folding and it also coordinates with the E3 ubiquitin ligase, STIP1 homology and U-box containing protein 1 (STUB1), to regulate oncoprotein degradation. We find that HSP70 binds a conserved ‘SELILKR’ motif and prevents the access of STUB1 on N-Myc possibly through steric hindrance. When HSP70’s dwell time on N-Myc is increased by the conformational change of HSP70, STUB1 is in close proximity with N-Myc and becomes functional to promote N-Myc ubiquitination on the K416 and K419 sites of the bHLH-LZ domain and form the poly ubiquitination chains linked by the K11 and K63 sites. Inhibition of HSP70’s ATPase activity by an allosteric inhibitor, JG231, promoted degradation of N-Myc through enhancing STUB1 binding in the nucleus. Notably, JG231 significantly suppressed NEPC tumor growth and limited expression of neuroendocrine related pathways. Guided by a potential bypass route of N-Myc turnover in the cancer cell, we find that dual targeting of Aurora kinase A (AURKA) and HSP70 drastically suppressed N-Myc and tumor growth in NEPC.

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Proteostasis perturbation of N-Myc by HSP70 inhibition improves treatment in neuroendocrine prostate cancer I

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Cytosolic splice isoform of Hsp70 nucleotide exchange factor Fes1 is required for the degradation of misfolded proteins in yeast

Project description:Cells maintain proteostasis by selectively recognizing and targeting misfolded proteins for degradation. In Saccharomyces cerevisiae, the Hsp70 nucleotide exchange factor Fes1 is essential for the degradation of chaperone-associated misfolded proteins by the ubiquitin-proteasome system. Here we show that the FES1 transcript undergoes unique 3' alternative splicing that results in two equally active isoforms with alternative C-termini, Fes1L and Fes1S. Fes1L is actively targeted to the nucleus and represents the first identified nuclear Hsp70 nucleotide exchange factor. In contrast, Fes1S localizes to the cytosol and is essential to maintain proteostasis. In the absence of Fes1S, the heat-shock response is constitutively induced at normally non-stressful conditions. Moreover, cells display severe growth defects when elevated temperatures, amino acid analogues or the ectopic expression of misfolded proteins, induce protein misfolding. Importantly, misfolded proteins are not targeted for degradation by the ubiquitin-proteasome system. These observations support the notion that cytosolic Fes1S maintains proteostasis by supporting the removal of toxic misfolded proteins by proteasomal degradation. This study provides key findings for the understanding of the organization of protein quality control mechanisms in the cytosol and nucleus. 4 strains (WT, fes1Î, fes1ÎS, fes1ÎL) were sequenced in triplicates from independent RNA isolations.

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Project description:RNA interference (RNAi) is a cell-intrinsic antiviral defense conserved in diverse organisms. However, the mechanism by which mammalian antiviral RNAi is regulated is largely unknown. Herein, we uncover that STUB1, an E3 ubiquitin ligase, interacts with and ubiquitinates AGO2, the core component of RNAi pathway, resulting in the degradation of AGO2 via ubiquitin-proteasome system. Additionally, STUB1 can induce the degradation of the other mammalian AGO proteins including AGO1, AGO3, and AGO4. Our further study reveals that STUB1 also interacts with and mediates the ubiquitination of Dicer, the endoribonuclease responsible for siRNA or miRNA biogenesis, via K48-linked poly-ubiquitin, which induces the degradation of Dicer and its specialized form, termed antiviral Dicer (aviDicer) that usually expresses in stem cells. Loss of STUB1 upregulated Dicer and AGO2, thereby enhancing antiviral RNAi to effectively inhibit viral RNA replication in mammalian cells. In vivo, the STUB1 deficiency markedly enhanced the production of virus-derived siRNAs and elicited a potent antiviral effect against Enterovirus-A71 (EV-A71) infection in newborn mouse. Our findings demonstrate STUB1 as a novel negative regulator of RNAi by mediating the ubiquitination and degradation of Dicer and AGO proteins, and provide novel insights into the regulatory mechanism of antiviral RNAi in mammals.

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Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer

Project description:Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer

| PRJNA491273 | ENA

Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer (Affymetrix)

Project description:Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer (Affymetrix)

| PRJNA491275 | ENA

Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer (RNA-Seq)

Project description:Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer (RNA-Seq)

| PRJNA491274 | ENA

Proteostasis perturbation of N-Myc by HSP70 inhibition improves treatment in neuroendocrine prostate cancer

Project description:N-Myc is a key driver of neuroendocrine tumors, such as neuroblastoma and neuroendocrine prostate cancer. However, N-Myc is considered undruggable because it lacks clear binding sites for small molecules. One potential way to circumvent this challenge is to identify and target the protein homeostasis proteostasis systems that maintain N-Myc levels. Here we developed a novel spontaneously indefinite prostate cancer cell line UCDCaP and its paired castration-resistant line UCDCaP-CR, which exhibits neural lineage plasticity and high levels of N-Myc protein expression. Through rapid immunoprecipitation mass spectrometry assay, we revealed that heat shock protein 70, HSP70 is a top partner for N-Myc. HSP70 is known to function in protein folding and it also coordinates with the E3 ubiquitin ligase, STIP1 homology and U-box containing protein 1, STUB1, to regulate oncoprotein degradation. We find that HSP70 binds a conserved SELILKR motif and prevents the access of STUB1 on N-Myc possibly through steric hindrance. When HSP70 dwell time on N-Myc is increased by the conformational change of HSP70, STUB1 is in close proximity with N-Myc and becomes functional to promote N-Myc ubiquitination on the K416 and K419 sites of the bHLH-LZ domain and form the poly ubiquitination chains linked by the K11 and K63 sites.

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Project description:The purpose of this study was to characterize the downstream transcriptomic effects of ARVib-mediated degradation of AR/AR-V7, particularly in attenuating AR/AR-V7 target gene expression in prostate cancer cells. Towards this goal, next-generation sequencing (NGS)-based gene expression profiling (RNA-Sequencing; RNA-Seq) was performed on castration-resistant prostate cancer (CRPC) C4-2B MDVR cells that were treated with vehicle control or one of the AR/AR-V7 inhibitors (ARVib), ARVib-7 or ARVib-31.

2021-08-22 | GSE158556 | GEO

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