SPOP Promotes Ubiquitination and Degradation of the ERG Oncoprotein to Suppress Prostate Cancer Progression

Gan, Wenjian; Dai, Xiangpeng; Lunardi, Andrea; Li, Zhen; Inuzuka, Hiroyuki; Liu, Pengda; Varmeh, Shoreh; Zhang, Jinfang; Liu, Cheng; Sun, Yin; Asara, John M.; Beck, Andrew H.; Huang, Jiaoti; Pandolfi, Pier Paolo; Wei, Wenyi

doi:10.1016/j.molcel.2015.07.026

Cited by 181 publications

(221 citation statements)

References 40 publications

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“…extends N-terminal of the phosphodegron motif, which would likely confer stronger binding (61,62). Several E3 ligases recognize their substrates through a multisite substrate recognition mechanism.…”

Section: The Complexity Of Degron Regulationmentioning

confidence: 99%

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Degrons in cancer

et al. 2017

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Degrons are the elements that are used by E3 ubiquitin ligases to target proteins for degradation. Most degrons are short linear motifs embedded within the sequences of modular proteins. As regulatory sites for protein abundance, they are important for many different cellular processes, such as progression through the cell cycle and monitoring cellular hypoxia. Degrons enable the elimination of proteins that are no longer required, preventing their possible dysfunction. Although the human genome encodes~600 E3 ubiquitin ligases, only a fraction of these enzymes have well-defined target degrons. Thus, for most cellular proteins, the destruction mechanisms are poorly understood. This is important for many diseases, especially for cancer, a disease that involves the enhanced expression of oncogenes and the persistence of encoded oncoproteins coupled with reduced abundance of tumor suppressors. Lossof-function mutations occur in the degrons of several oncoproteins, such as the transcription factors MYC and NRF2, and in various mitogenic receptors, such as NOTCH1 and several receptor tyrosine kinases. Mutations eliminating the function of the b-catenin degron are found in many cancers and are considered one of the most abundant mutations driving carcinogenesis. In this Review, we describe the current knowledge of degrons in cancer and suggest that increased research on the "dark degrome" (unknown degron-E3 relationships) would enhance progress in cancer research.

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Section: The Complexity Of Degron Regulationmentioning

confidence: 99%

“…The diminished or abolished degradation eventually leads to the accumulation of these fusion proteins, which drives prostate cancer metastasis (61,62). TMPRSS2 also forms genetic fusions through chromosomal translocation with the gene encoding ETV1.…”

Section: Modulation Of Protein Degradation In Cancermentioning

confidence: 99%

Degrons in cancer

et al. 2017

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“…Most interestingly, EWS-FLI1 displays a higher turnover compared with its full-length proteins EWSR1 and FLI1. In contrast, the ETS proteins ERG and ETV1, which are fused to the TMPRSS2 promoter in prostate cancer, stabilize the protein and confer a physiological advantage to cancer cells (33,34,36). The truncated protein versions display increased stability due to loss of the N-terminal E3 ligase motif.…”

Section: Ews-fli1 Degradation Is Mediated By One Lysine Residuementioning

confidence: 99%

“…Several ETS proteins can be polyubiquitinated by different E3 ligases and subsequently degraded by the proteasome (33)(34)(35)(36). Considering their high conservation, proteasomal degradation is likely to be the main mechanism of turnover for most ETS family members.…”

mentioning

confidence: 99%

“…Considering their high conservation, proteasomal degradation is likely to be the main mechanism of turnover for most ETS family members. Most interestingly, truncated ERG and ETV1 lack the N-terminal E3 binding domain, which results in a delayed turnover of aberrant ETS proteins (34,36). Here, we focus specifically on the turnover of the fusion protein EWS-FLI1, which only harbors the ETS and the C-terminal domain from FLI1.…”

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confidence: 99%

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Proteasomal Degradation of the EWS-FLI1 Fusion Protein Is Regulated by a Single Lysine Residue

Gierisch

Pfistner

Lopez-Garcia

et al. 2016

Journal of Biological Chemistry

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Edited by George DeMartinoEHere, we identify the EWS-FLI1 protein as a substrate of the ubiquitin-proteasome system with a characteristic polyubiquitination pattern. Using a global protein stability approach, we determined the half-life of EWS-FLI1 to lie between 2 and 4 h, whereas full-length EWSR1 and FLI1 were more stable. By mass spectrometry, we identified two ubiquitin acceptor lysine residues of which only mutation of Lys-380 in the ETS domain of the FLI1 part abolished EWS-FLI1 ubiquitination and stabilized the protein posttranslationally. Expression of this highly stable mutant protein in Ewing cells while simultaneously depleting the endogenous wild type protein differentially modulates two subgroups of target genes to be either EWS-FLI1 protein-dependent or turnover-dependent. The majority of target genes are in an unaltered state and cannot be further activated. Our study provides novel insights into EWS-FLI1 turnover, a critical pathway in Ewing sarcoma pathogenesis, and lays new ground to develop novel therapeutic strategies in Ewing sarcoma. E-26 transformation-specific (ETS)2 family members are strong activators or repressors of transcription with a highly conserved ETS domain (1-3). ETS transcription factors (TFs) bind most commonly in complexes to a GGA core region to mediate gene expression (4, 5). Their main biological functions include regulation of differentiation, lineage determination of the hematopoietic system, and control of angiogenesis (6, 7). Most of the ETS family members have oncogenic potential because truncated or overexpressed ETS proteins have been linked to several cancer entities (8 -11). ERG and ETV1 are frequently fused to the TMPRSS2 promoter in prostate cancer, whereas ETV1 and ETV6 are implicated in leukemia (12, 13). Like other aberrant fusion proteins, they act as drivers of uncontrolled cell growth and survival (14, 15). However, most TFs do not harbor an enzymatic pocket and are therefore difficult to target directly. Novel strategies that uncover vulnerable sites in TFs are urgently needed to develop novel targeted therapies (16).Ewing sarcoma is a rare pediatric bone and soft tissue tumor with an aggressive behavior and prevalence to metastasize (17,18). Its main genetic abnormalities are EWS-ETS rearrangements, among them most commonly the EWS gene on chromosome 22 fused to FLI1 on chromosome 11, which results in expression of the chimeric transcription factor . Continuous expression of the fusion protein is crucial for tumor formation, progression, and maintenance (22, 23), and its down-regulation inhibits proliferation and reduces tumor cell growth (24 -26). EWS-FLI1 is thought to function mainly as a modulator to activate and repress a wide range of target genes but also as a regulator of splicing processes or as a component of large interaction networks (27-31). However, inhibition of a single downstream target gene has not been proven effective yet for Ewing sarcoma therapy.The turnover of most intracellular proteins is mediated via the ubiquitin-proteasome ...

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Deubiquitinase OTUD6A promotes proliferation of cancer cells via regulating Drp1 stability and mitochondrial fission

et al. 2020

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Dynamin-related protein 1 (Drp1) is a cytosolic protein responsible for mitochondrial fission and is essential in the initiation and development of several human diseases, including cancer. However, the regulation of Drp1, especially of its ubiquitination, remains unclear. In this study, we report that the ovarian tumor-associated protease deubiquitinase 6A (OTUD6A) deubiquitylates and stabilizes Drp1, thereby facilitating regulation of mitochondrial morphology and tumorigenesis. OTUD6A is upregulated in human patients with colorectal cancer. Depletion of OTUD6A leads to lower Drp1 levels and suppressed mitochondrial fission and the affected cells are consequently less prone to tumorigenesis. Conversely, overexpression of OTUD6A increases Drp1 levels and its protein half-life and enhances cancer cell growth. Therefore, our results reveal a novel upstream protein of Drp1, and its role in tumorigenesis that is played, in part, through the activation of mitochondrial fission mediated by Drp1.

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SPOP Promotes Ubiquitination and Degradation of the ERG Oncoprotein to Suppress Prostate Cancer Progression

Cited by 181 publications

References 40 publications

Degrons in cancer

Degrons in cancer

Proteasomal Degradation of the EWS-FLI1 Fusion Protein Is Regulated by a Single Lysine Residue

Deubiquitinase OTUD6A promotes proliferation of cancer cells via regulating Drp1 stability and mitochondrial fission

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