Deubiquitinating Enzyme-Mediated Signaling Networks in Cancer Stem Cells

Kaushal, Kamini; Ramakrishna, Suresh

doi:10.3390/cancers12113253

Cited by 8 publications

(7 citation statements)

References 225 publications

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“…Deubiquitinating enzymes (DUBs) mediate the removal of ubiquitin from targeted ubiquitylated substrates to regulate their activities. DUBs control the expression, localization, and activity of numerous proteins and participate in various cellular processes, including the growth, cell cycle, signal transduction, and apoptosis [ 3 , 4 ]. Moreover, growing body of evidence suggests that the dysfunction of the DUB system can degrade tumor suppressors and elevate oncoprotein levels [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Ubiquitin Specific Protease 29 Functions as an Oncogene Promoting Tumorigenesis in Colorectal Carcinoma

Chandrasekaran

Suresh

Sarodaya

et al. 2021

Cancers

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Colorectal carcinoma is the third foremost cause of cancer-related deaths and accounts for 5.8% of all deaths globally. The molecular mechanisms of colon cancer progression and metastasis control are not well studied. Ubiquitin-specific protease 29 (USP29), a deubiquitinating enzyme, is involved in the occurrence and development of wide variety of cancers. However, its clinical significance and biological roles in colorectal carcinoma (CRC) remain unexplored. In this research, we observed that the rate of USP29 overexpression was higher in colon cancer patient tissues relative to its corresponding normal tissues. CRISPR-Cas9-mediated depletion of USP29 triggered DNA double strand breaks and delayed cell-cycle progression in HCT116 cells. We also demonstrated that USP29 depletion hampers the colony formation and increases apoptosis of HCT116 cells. USP29 knockdown significantly decreased CRC cell proliferation in vitro. Depletion of USP29 in HCT116 cells substantially reduced the tumor volume of mouse xenografts. In conclusion, our study shows that elevated expression of USP29 promotes malignancy in CRC, suggesting that USP29 could be a promising target for colon cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Ubiquitin Specific Protease 29 Functions as an Oncogene Promoting Tumorigenesis in Colorectal Carcinoma

Chandrasekaran

Suresh

Sarodaya

et al. 2021

Cancers

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“…The balanced control over ubiquitination and deubiquitination processes of stem cell transcription factors determines cell fate [43]. Ubiquitination of stem cell transcription factors by E3 ligases results in stem cell differentiation, while DUB activity prevents proteolysis and stabilizes stem cell transcription factors to maintain stemness [23,43,44].…”

Section: Discussionmentioning

confidence: 99%

“…A later study demonstrated that the protein inhibitor of activated STAT1 (PIAS1) negatively regulates the ubiquitination of MSX1 homeoprotein in a SUMO-independent manner [21]. Moreover, ubiquitination is a key process for maintaining the protein levels of any substrate by regulating its protein turnover [22,23]. The loss of function of any gene related to UPS results in the development of various diseases, including neurodegenerative disease, cancers, and osteoporosis [24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Genome-Wide CRISPR/Cas9-Based Screening for Deubiquitinase Subfamily Identifies Ubiquitin-Specific Protease 11 as a Novel Regulator of Osteogenic Differentiation

Kaushal

Tyagi

Karapurkar

et al. 2022

IJMS

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The osteoblast differentiation capacity of mesenchymal stem cells must be tightly regulated, as inadequate bone mineralization can lead to osteoporosis, and excess bone formation can cause the heterotopic ossification of soft tissues. The balanced protein level of Msh homeobox 1 (MSX1) is critical during normal osteogenesis. To understand the factors that prevent MSX1 protein degradation, the identification of deubiquitinating enzymes (DUBs) for MSX1 is essential. In this study, we performed loss-of-function-based screening for DUBs regulating MSX1 protein levels using the CRISPR/Cas9 system. We identified ubiquitin-specific protease 11 (USP11) as a protein regulator of MSX1 and further demonstrated that USP11 interacts and prevents MSX1 protein degradation by its deubiquitinating activity. Overexpression of USP11 enhanced the expression of several osteogenic transcriptional factors in human mesenchymal stem cells (hMSCs). Additionally, differentiation studies revealed reduced calcification and alkaline phosphatase activity in USP11-depleted cells, while overexpression of USP11 enhanced the differentiation potential of hMSCs. These results indicate the novel role of USP11 during osteogenic differentiation and suggest USP11 as a potential target for bone regeneration.

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“…Stem-like cells, which are characterised by the self-renewal properties and therapeutic resistance, play crucial roles in various cancers, ( Kaushal and Ramakrishna, 2020 ), especially in GBM ( Wang et al, 2018 ). Although cancer stem-like cells are very important for prognosis in GBM, ( Turaga et al, 2020 ), there are still some shortcomings and complications in quantifying these cells.…”

Section: Introductionmentioning

confidence: 99%

Prognostic Value of mRNAsi/Corrected mRNAsi Calculated by the One-Class Logistic Regression Machine-Learning Algorithm in Glioblastoma Within Multiple Datasets

Zhang

Chen

Liang

et al. 2021

Front. Mol. Biosci.

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Glioblastoma (GBM) is the most common glial tumour and has extremely poor prognosis. GBM stem-like cells drive tumorigenesis and progression. However, a systematic assessment of stemness indices and their association with immunological properties in GBM is lacking. We collected 874 GBM samples from four GBM cohorts (TCGA, CGGA, GSE4412, and GSE13041) and calculated the mRNA expression-based stemness indices (mRNAsi) and corrected mRNAsi (c_mRNAsi, mRNAsi/tumour purity) with OCLR algorithm. Then, mRNAsi/c_mRNAsi were used to quantify the stemness traits that correlated significantly with prognosis. Additionally, confounding variables were identified. We used discrimination, calibration, and model improvement capability to evaluate the established models. Finally, the CIBERSORTx algorithm and ssGSEA were implemented for functional analysis. Patients with high mRNAsi/c_mRNAsi GBM showed better prognosis among the four GBM cohorts. After identifying the confounding variables, c_mRNAsi still maintained its prognostic value. Model evaluation showed that the c_mRNAsi-based model performed well. Patients with high c_mRNAsi exhibited significant immune suppression. Moreover, c_mRNAsi correlated negatively with infiltrating levels of immune-related cells. In addition, ssGSEA revealed that immune-related pathways were generally activated in patients with high c_mRNAsi. We comprehensively evaluated GBM stemness indices based on large cohorts and established a c_mRNAsi-based classifier for prognosis prediction.

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Deubiquitinating Enzyme-Mediated Signaling Networks in Cancer Stem Cells

Cited by 8 publications

References 225 publications

Ubiquitin Specific Protease 29 Functions as an Oncogene Promoting Tumorigenesis in Colorectal Carcinoma

Ubiquitin Specific Protease 29 Functions as an Oncogene Promoting Tumorigenesis in Colorectal Carcinoma

Genome-Wide CRISPR/Cas9-Based Screening for Deubiquitinase Subfamily Identifies Ubiquitin-Specific Protease 11 as a Novel Regulator of Osteogenic Differentiation

Prognostic Value of mRNAsi/Corrected mRNAsi Calculated by the One-Class Logistic Regression Machine-Learning Algorithm in Glioblastoma Within Multiple Datasets

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