UCHL1 as a novel target in breast cancer: emerging insights from cell and chemical biology

Mondal, Milon; Conole, Daniel; Nautiyal, Jaya; Tate, Edward W.

doi:10.1038/s41416-021-01516-5

Cited by 41 publications

(38 citation statements)

References 104 publications

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“…Ubiquitin carboxyl-terminal hydrolase L1 inhibition is being experimentally tested for its antifibrotic property ( 12 – 15 ) and explored as a potentially new anti-malignancy strategy ( 9 ). The findings of the present study implicate that the UCHL1 inhibition probably can be tolerated by normal hearts because the complete loss of function of UCHL1 in cardiomyocytes did not show discernible abnormality; however, such a treatment should be watched for cardiotoxicity if the subject has cardiac co-morbidities because UCHL1 deficiency does impair cardiac proteostasis when the heart is under a stress condition such as ischemic heart disease.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in the UCHL1 gene are linked to neurodegenerative disease, such as an early-onset progressive neurodegeneration syndrome ( 7 ) and familial Parkinson’s disease ( 8 ). UCHL1 gain-of-function has been connected to the genesis of various types of tumor, including breast cancer ( 9 ), ovarian cancer ( 10 ), and lymphoma ( 11 ); hence, UCHL1 is regarded as an oncogene ( 11 ). Accordingly, inhibition of UCHL1 is being intensively studied as a potential anticancer strategy, which is further fueled by the commercial availability of UCHL1-specific chemical inhibitors ( 6 , 9 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

“…UCHL1 gain-of-function has been connected to the genesis of various types of tumor, including breast cancer ( 9 ), ovarian cancer ( 10 ), and lymphoma ( 11 ); hence, UCHL1 is regarded as an oncogene ( 11 ). Accordingly, inhibition of UCHL1 is being intensively studied as a potential anticancer strategy, which is further fueled by the commercial availability of UCHL1-specific chemical inhibitors ( 6 , 9 , 12 ). UCHL1 inhibitors are also being tested for their anti-fibrotic effects ( 12 – 15 ).…”

Section: Introductionmentioning

confidence: 99%

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Ubiquitin Carboxyl-Terminal Hydrolase L1 of Cardiomyocytes Promotes Macroautophagy and Proteostasis and Protects Against Post-myocardial Infarction Cardiac Remodeling and Heart Failure

Cai

et al. 2022

Front. Cardiovasc. Med.

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Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a deubiquitinase known to play essential roles in the nervous tissue. Myocardial upregulation of UCHL1 was observed in human dilated cardiomyopathy and several animal models of heart disease, but the (patho)physiological significance of UCHL1 in cardiomyocytes remains undefined. Hence, we conducted this study to fill this critical gap. We produced cardiomyocyte-restricted Uchl1 knockout (CKO) by coupling the Uchl1-floxed allele with transgenic Myh6-Cre in C57B/6J inbred mice. Mice transgenic for Myh6-Cre were used as controls (CTL). Myocardial Uchl1 proteins were markedly reduced in CKO mice but they did not display discernible abnormal phenotype. Ten-week old CTL or CKO mice were subjected to left anterior descending artery ligation (myocardial infarction, MI) or sham surgery (Sham) and characterized at 7- and 28-day after surgery. Compared with Sham mice, significant increases in myocardial UCHL1 proteins were detected in CTL MI but not in CKO MI mice. MI-induced left ventricular (LV) chamber dilation, reduction of ejection fraction (EF) and fractional shortening (FS), and LV anterior wall thinning detected by echocardiography were comparable between the CTL MI and CKO MI groups 7-day post-MI. However, by 28-day post-MI, MI-induced LV chamber dilatation, EF and FS reduction, increases of myocardial ubiquitin conjugates, and increases in the heart weight to body weight ratio and the ventricular weight to body weight ratio were significantly more pronounced in CKO MI than CTL MI mice. As further revealed by LV pressure-volume relationship analyses, CKO MI mice but not CTL MI mice displayed significant decreases in stroke volume, cardiac output, and the maximum rates of LV pressure rising or declining and of LV volume declining, as well as significant increases in LV end-diastolic pressure and Tau, compared with their respective Sham controls. LC3-II flux assays reveal that autophagic flux is decreased in CKO mouse myocardium as well as in cultured Uchl1-deficient cardiomyocytes. In conclusion, UCHL1 of cardiomyocytes is dispensable for development but promotes macroautophagy in cardiomyocytes. Upregulation of UCHL1 in post-MI hearts occurs primarily in the cardiomyocytes and protects against post-MI cardiac remodeling and malfunction likely through supporting autophagic flux and proteostasis during a stress condition.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ubiquitin Carboxyl-Terminal Hydrolase L1 of Cardiomyocytes Promotes Macroautophagy and Proteostasis and Protects Against Post-myocardial Infarction Cardiac Remodeling and Heart Failure

Cai

et al. 2022

Front. Cardiovasc. Med.

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“…Large ubiquitinated proteins cannot be bound or catalyzed to the same extent as smaller ubiquitinated proteins due to the small and tight pocket on the active site of UCHs and the restriction of the loop diameter ( Bishop et al., 2016 ; Lou et al., 2016 ). The UCHs and many USPs share a similarly three-dimensional design and a superimposable catalytic triad, however, they differ in the amino acid sequence of the catalytic positions ( Amerik and Hochstrasser, 2004 ; Mondal et al., 2022 126(1). The sequence similarity of UCHL1 DUBs is limited to the domain containing the catalytic triad of Cys, His, and Asp/Asn residues.…”

Section: Functional Role Of Important Dub Domains In Humanmentioning

confidence: 99%

The emerging role of Deubiquitinases (DUBs) in parasites: A foresight review

Kumar

Mandal

et al. 2022

Front. Cell. Infect. Microbiol.

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Before the discovery of the proteasome complex, the lysosomes with acidic proteases and caspases in apoptotic pathways were thought to be the only pathways for the degradation of damaged, unfolded, and aged proteins. However, the discovery of 26S and 20S proteasome complexes in eukaryotes and microbes, respectively, established that the degradation of most proteins is a highly regulated ATP-dependent pathway that is significantly conserved across each domain of life. The proteasome is part of the ubiquitin-proteasome system (UPS), where the covalent tagging of a small molecule called ubiquitin (Ub) on the proteins marks its proteasomal degradation. The type and chain length of ubiquitination further determine whether a protein is designated for further roles in multi-cellular processes like DNA repair, trafficking, signal transduction, etc., or whether it will be degraded by the proteasome to recycle the peptides and amino acids. Deubiquitination, on the contrary, is the removal of ubiquitin from its substrate molecule or the conversion of polyubiquitin chains into monoubiquitin as a precursor to ubiquitin. Therefore, deubiquitylating enzymes (DUBs) can maintain the dynamic state of cellular ubiquitination by releasing conjugated ubiquitin from proteins and controlling many cellular pathways that are essential for their survival. Many DUBs are well characterized in the human system with potential drug targets in different cancers. Although, proteasome complex and UPS of parasites, like plasmodium and leishmania, were recently coined as multi-stage drug targets the role of DUBs is completely unexplored even though structural domains and functions of many of these parasite DUBs are conserved having high similarity even with its eukaryotic counterpart. This review summarizes the identification & characterization of different parasite DUBs based on in silico and a few functional studies among different phylogenetic classes of parasites including Metazoan (Schistosoma, Trichinella), Apicomplexan protozoans (Plasmodium, Toxoplasma, Eimeria, Cryptosporidium), Kinetoplastidie (Leishmania, Trypanosoma) and Microsporidia (Nosema). The identification of different homologs of parasite DUBs with structurally similar domains with eukaryotes, and the role of these DUBs alone or in combination with the 20S proteosome complex in regulating the parasite survival/death is further elaborated. We propose that small molecules/inhibitors of human DUBs can be potential antiparasitic agents due to their significant structural conservation.

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“…In terms of historical classification, to a large extent, breast carcinogenesis is based on the oncogenic activity of estrogen receptor α (ERα) as well as other hormone receptors, progesterone receptor (PR) and human epidermal growth factor receptor 2(HER2/ERBB2). Based on the expression of these proteins, breast cancers are classically classified into five subtypes: luminal A (ER+, PR+, HER2-), luminal B (ER+, PR-, HER2+), HER2-positive (ER-, PR-, HER2+), basal-like and triple-negative breast cancers (ER-, PR- and HER2-), while the last two subtypes are similar but distinct from invasive breast cancer ( 4 ).Currently, the treatment strategies for breast cancer are determined mainly based on tumor size, morphology, metastasis and expression of ER, PR, Ki67 and HER2, including surgery, radiotherapy, endocrine therapy and chemotherapy, which have led to a great delay in tumor progression and further improvement in patient survival ( 5 ).However, these therapeutic strategies have not been clinically effective, so there is an urgent need to explore additional molecular regulatory mechanisms of breast cancer to develop new diagnostic and therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

The function and regulatory mechanism of RNA-binding proteins in breast cancer and their future clinical treatment prospects

Zhong

Liu

et al. 2022

Front. Oncol.

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Breast cancer is the most common female malignancy, but the mechanisms regulating gene expression leading to its development are complex. In recent years, as epigenetic research has intensified, RNA-binding proteins (RBPs) have been identified as a class of posttranscriptional regulators that can participate in regulating gene expression through the regulation of RNA stabilization and degradation, intracellular localization, alternative splicing and alternative polyadenylation, and translational control. RBPs play an important role in the development of normal mammary glands and breast cancer. Functional inactivation or abnormal expression of RBPs may be closely associated with breast cancer development. In this review, we focus on the function and regulatory mechanisms of RBPs in breast cancer, as well as the advantages and challenges of RBPs as potential diagnostic and therapeutic targets in breast cancer, and discuss the potential of RBPs in clinical treatment.

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UCHL1 as a novel target in breast cancer: emerging insights from cell and chemical biology

Cited by 41 publications

References 104 publications

Ubiquitin Carboxyl-Terminal Hydrolase L1 of Cardiomyocytes Promotes Macroautophagy and Proteostasis and Protects Against Post-myocardial Infarction Cardiac Remodeling and Heart Failure

Ubiquitin Carboxyl-Terminal Hydrolase L1 of Cardiomyocytes Promotes Macroautophagy and Proteostasis and Protects Against Post-myocardial Infarction Cardiac Remodeling and Heart Failure

The emerging role of Deubiquitinases (DUBs) in parasites: A foresight review

The function and regulatory mechanism of RNA-binding proteins in breast cancer and their future clinical treatment prospects

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