Deubiquitinating enzymes in cancer stem cells: functions and targeted inhibition for cancer therapy

Kaushal, Kamini; Antao, Ainsley Mike; Kim, Kye Seong; Ramakrishna, Suresh

doi:10.1016/j.drudis.2018.05.035

Cited by 40 publications

(25 citation statements)

References 119 publications

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“…Though, role of PSMA7 in evolutionarily conserved proteasome isoform with increased proteasome activity has been reported [53]. Deubiquitinating enzymes are important regulators of gene transcription [58]. Ataxin 3 is a deubiquitinating enzyme as well as transcriptional co-repressor, which is involved in protein homeostasis [59].…”

Section: Discussionmentioning

confidence: 99%

Deubiquitinase UCHL1 Maintains Protein Homeostasis through PSMA7-APEH-Proteasome Axis in High-Grade Serous Ovarian Carcinoma

Tangri

Lighty

Loganathan

et al. 2020

Preprint

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High-grade serous ovarian cancer (HGSOC) is characterized by genomic instability, DNA damage, oxidative stress, and high metabolic demand that contribute to misfolded proteins and proteotoxicity. However, the underlying mechanisms that maintain protein homeostasis to promote HGSOC growth remain poorly understood. In this study, we report that the neuronal deubiquitinating enzyme, UCHL1 (ubiquitin C-terminal hydrolase L1) is overexpressed in HGSOC and regulates protein homeostasis. UCHL1 expression was markedly increased in HGSOC patient tumors and serous tubal intraepithelial carcinoma (HGSOC precursor lesions) and correlated with higher tumor grade and poor patient survival. UCHL1 inhibition reduced proliferation and invasion of HGSOC cells as well as significantly reduced the in vivo metastatic growth of the ovarian cancer xenografts. Transcriptional profiling of UCHL1 silenced HGSOC cells revealed down-regulation of genes implicated with proteasome activity along with the upregulation of endoplasmic reticulum (ER) stress-mediated genes. Silencing UCHL1 resulted in reduced expression of proteasome subunit alpha 7 (PSMA7) and acylaminoacyl peptide hydrolase (APEH) leading to a decrease in proteasome activity, accumulation of polyubiquitinated proteins, and reduced mTORC1 activity and protein synthesis. This induced ER-stress mediated pro-apoptotic factors, including ATF3 (activating transcription factor 3). In addition, the growth of HGSOC cells was significantly reduced upon silencing PSMA7 and APEH or inhibiting proteasome activity. Together, these results indicate that the UCHL1-PSMA7-APEH axis mediates the degradation of misfolded proteins, salvage amino acids for protein synthesis, and maintain protein homeostasis. This study highlights protein homeostasis as a therapeutic vulnerability in HGSOC and identifies UCHL1 and APEH inhibitors as novel therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Deubiquitinase UCHL1 Maintains Protein Homeostasis through PSMA7-APEH-Proteasome Axis in High-Grade Serous Ovarian Carcinoma

Tangri

Lighty

Loganathan

et al. 2020

Preprint

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“…Subsequent studies attributed the pharmacological activity of WP1130 to its inhibition of the deubiquitinase activity of USP9X, USP5, USP14, and UCH37 (20). The partially selective deubiquitinase inhibition by WP1130 has been explored for cancer therapy, as WP1130 exhibits anticancer effects both as monotherapy and in combination with other modalities, such as chemotherapy, in preclinical models of a variety of cancer types, including glioblastoma (10,11,21). Chen and colleagues now provide a mechanistic insight and rationale for the therapeutic inhibition of USP9X in cancers driven or sustained by ALDH1A3, represented by mesenchymal GSCs and glioblastoma.…”

Section: Role Of Usp9x In Human Mesenchymal Gscsmentioning

confidence: 99%

“…Their work is, however, unique as it for the first time identified a posttranslational molecular mechanism that regulates ALDH1A3; the deubiquitinase enzyme USP9X promotes the stability of ALDH1A3 by removing "degrons" (linkage-specific degradation signals), preventing its degradation by the proteasome (9). USP9X, also called FAM, is encoded by USP9X, located on the X chromosome, and a member of the ubiquitin-specific proteases (USP) family that makes up the largest subclass of DUBs and is implicated in the regulation of carcinogenesis and cancer stem cells (10,11). Accumulating evidence supports oncogenic roles of USP9X, as it promotes TGF-β/ SMAD4 signaling (12) and epithelial/mesenchymal transition (13) and stabilizes antiapoptotic protein MCL1 (14) and the family of the inhibitors of apoptosis proteins (IAPS) (e.g., XIAP) (15).…”

Section: Inhibition Of Usp9x In Aldh1a3-driven Cancersmentioning

confidence: 99%

Deubiquitinating ALDH1A3 key to maintaining the culprit of aggressive brain cancer

Wakimoto¹

2019

Journal of Clinical Investigation

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“…SVV has been identified as a novel oncolytic virus against several human cancers (Burke, 2016). Ubiquitination and deubiquitination are mechanisms that also play important roles in regulation of cancer (Kaushal et al, 2018). Whether SVV can inhibit cancer progression through 3C pro DUB activity is still unclear and will need to be investigated in future studies.…”

Section: Primersmentioning

confidence: 99%

Seneca Valley Virus 3C protease negatively regulates the type I interferon pathway by acting as a viral deubiquitinase

et al. 2018

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The mechanisms that enable Seneca Valley Virus (SVV) to escape the host innate immune response are not well known. Previous studies demonstrated that SVV 3C pro suppresses innate immune responses by cleavage of host proteins and degradation of IRF3 and IRF7 protein expression. Here, we showed that SVV 3C protease (3C pro ) has deubiquitinating activity. Overexpressed 3C pro inhibits the ubiquitination of cellular substrates, acting on both lysine-48-and lysine-63-linked polyubiquitin chains. SVV infection also possessed deubiquitinating activity. The ubiquitin-proteasome system was significantly involved in SVV replication. Furthermore, 3C pro inhibited the ubiquitination of retinoic acid-inducible gene I (RIG-I), TANK-binding kinase 1 (TBK1), and TNF receptor-associated factor 3 (TRAF3), thereby blocking the expression of interferon (IFN)-β and IFN stimulated gene 54 (ISG54) mRNAs. A detailed analysis revealed that mutations (H48A, C160A, or H48A/C160A) that ablate the Cys and His residues of 3C pro abrogated its deubiquitinating activity and the ability of 3C pro to block IFN-β induction.Together, our results demonstrate a novel mechanism developed by SVV 3C pro to promote viral replication, and may also provide a novel strategy for improving ubiquitination-based therapy.

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Deubiquitinating enzymes in cancer stem cells: functions and targeted inhibition for cancer therapy

Cited by 40 publications

References 119 publications

Deubiquitinase UCHL1 Maintains Protein Homeostasis through PSMA7-APEH-Proteasome Axis in High-Grade Serous Ovarian Carcinoma

Deubiquitinase UCHL1 Maintains Protein Homeostasis through PSMA7-APEH-Proteasome Axis in High-Grade Serous Ovarian Carcinoma

Deubiquitinating ALDH1A3 key to maintaining the culprit of aggressive brain cancer

Seneca Valley Virus 3C protease negatively regulates the type I interferon pathway by acting as a viral deubiquitinase

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