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Deubiquitinating Enzyme in HNSCC: History
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Contributor:
Shengjian Jin
, Yasusei Kudo , Taigo Horiguchi

Ubiquitin is a highly-conserved small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Ubiquitin was first identified in 1975. It performs its myriad functions through conjugation to a large range of target proteins. A variety of different modifications can occur. This discovery that ubiquitin can be attached to proteins and label them for destruction won the Nobel Prize for chemistry in 2004. The ubiquitin protein consists of 76 amino acids and has a molecular mass of about 8.5 kDa. Under the conditions where ATP provides energy, ubiquitin molecules bind to the target protein through the cascade catalytic reaction of ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3). The ubiquitinated target protein is recognized and degraded by 26S proteasome. Ubiquitination and deubiquitination are two popular ways for the post-translational modification of proteins. These two modifications affect intracellular localization, stability, and function of target proteins. The process of deubiquitination is involved in histone modification, cell cycle regulation, cell differentiation, apoptosis, endocytosis, autophagy, and DNA repair after damage. It is involved in the processes of carcinogenesis and cancer development. The deubiquitinating enzyme (DUB) function in head and neck squamous cell carcinoma (HNSCC) is discussed. 

  • HNSCC
  • deubiquitinating enzyme
  • cancer

1. The Role and Mechanism of Deubiquitinating Enzyme in Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) was the seventh most common type of cancer worldwide in 2018 [1], representing about 6% of all cases and accounting for an estimated 650,000 new cancer cases and 350,000 cancer deaths worldwide every year [2]. The pathogenic factors include tobacco and alcohol intake, human papillomavirus (HPV) or Epstein Barr virus (EBV) infection, radiation, periodontal disease, vitamin deficiency, and eating habits [3]. Achieving a better understanding of molecular aberrations that are associated with HNSCC might identify new diagnostic and therapeutic strategies for this disease. (Table 1, Figure 1) [4][5][6][7][8][9][10][11][12][13][14][15][16][17].
Ijms 24 00552 g002 550
Figure 1. Involvement of DUBs in HNSCC.
Table 1. DUB function in HNSCC.
DUB Abnormal
Regulation		 The Roles in HNSCC Substrates References
CYLD mutation removes K63-polyubiquitin and M1 linear-ubiquitin chains and inhibits NFκB signaling RIP1, TRAF2, TRAF6, TAK1, NEMO [4]
Low expression promotes TGF-β signaling and cell invasion ALK5 [5]
Low expression removes K63-polyubiquitin, thereby inhibiting TGF-β
signaling		 SMAD7 [6][15]
USP4 overexpression removes K63-polyubiquitin and promotes TNF-α induced apoptosis RIP1 [18]
USP7 overexpression promotes cell growth, cell migration, and invasion EZH2 [7][16]
USP9X overexpression deubiquitinates and stabilizes PD-L1 to promote cell
proliferation		 PD-L1 [19]
Low expression mTOR pathway   [20]
USP22 overexpression associates with lymph node metastasis and histological grade   [21]
USP28 overexpression inhibits p53 on the promoter of pro-apoptotic genes Np63 [8][9][10][11]
BAP1 overexpression deubiquitinates H2A at the DSB site suppresses
transcription, and promotes DNA repair		 H2Aub(K119) [22]
PSMD14 overexpression stabilizes E2F1, gives stemness to cells by SOX2 expression and Akt signal activation E2F1 [12]
PSMD7 overexpression a prognostic factor correlated with immune infiltration   [13]
OTUB1 overexpression a risk factor   [4][14][17]

2. The Role of Deubiquitinating Enzymes in Head and Neck Squamous Cell Carcinoma Cell Proliferation and Apoptosis

Cell cycle regulation, uncontrolled proliferation, and inhibition of apoptosis will affect the occurrence and development of tumors. USP22, which has been described as a cancer stem cell (CSC) marker [23][24], is a member of the largest subfamily of DUBs [25]. The USP22 gene is located on chromosome 17 and consists of 14 exons, can indirectly affect chromatin structure through histone ubiquitination (H2A and H2B), thus regulating the transcriptional activation of many genes and widely affecting biological functions [21]. USP22 has the protein characteristics of CSCs and can promote the formation of various proteins for invasive tumor growth [26]. In addition, USP22 has been shown to regulate cellular growth and proliferation. Indeed, USP22 depletion reduces transformation of c-Myc and plays an important role in cell cycle progression and anchorage-independent growth [27]. Additionally, the downregulation of USP22 results in tumor cells remaining arrested at the G1 phase via p21 stabilization [28][29]. Thus, USP22 plays an important role in cell cycle regulation. The depletion of USP22 in HNSCC tissue can affect the CDK inhibitor (CDKI)/Rb signal pathway. USP22 increases the expression of cyclin-dependent kinase inhibitor 1A (CDKI) including p21 and p27, and it decreases the expression of Rb protein in HNSCC cells [29][30][31]. An immunohistochemical study showed that USP22 expression is upregulated in laryngeal carcinoma and has a close relationship with malignant behaviors including invasion, metastasis, and poor prognosis [32].
Ubiquitin-specific protease 9X (USP9X) is related to the occurrence and development of pancreatic cancer, multiple myeloma, and other tumors [33]. USP9X knockdown in HNSCC cells decreases the percentage of cells in the G0/G1 phase and increases the percentage of cells in the S and G2/M phase. The proliferation of HNSCC cells can be regulated by downstream transcription factor HES-1 (Notch pathway) through USP9X level [20]. USP9X may also regulate the proliferation of HNSCC through the mammalian target of the rapamycin (mTOR) pathway [32][34]. However, the loss of USP9X may be harmful to the growth of tumor cells, but its loss in primary tumor cells may accelerate the development of secondary tumors [35].
USP14 has been proven to be related to the occurrence and development of many cancers. In tumor xenograft mice, the growth of HNSCC with low USP14 was slower than that of the control group. The expression of USP14 in tongue carcinoma was higher than that in adjacent tissues. USP14 depletion can inhibit the proliferation and migration of HNSCC cells in vitro [36]. Moreover, USP14 can promote the proliferation and invasion of HNSCC both in vivo and in vitro.
Ubiquitin-specific peptidase 4 (USP4) has been identified to deubiquitinate K63-linked ubiquitin conjugates from TNF receptor-associated factor 2 (TRAF2), TNF receptor associated factor 6 (TRAF6), and TGF-beta activated kinase 1 (TAK1) and stabilizes molecules by deubiquitinating K48-linked ubiquitination [18]. USP4 is significantly upregulated in tumor tissues compared to matched non-tumor tissues in HNSCC. Co-immunoprecipitation showed that USP4 interacted with receptor-interacting protein 1 (RIPI) to remove K63-connected ubiquitin molecules to stabilize RIPI expression. Thus, it negatively regulates the activation of NF-κB mediated by deubiquitination of RIPI. These findings indicate that USP4 has tumor suppressor roles in HNSCC [18].

3. Relationship between Deubiquitinating Enzymes and Prognosis of Head and Neck Squamous Cell Carcinoma

The prognosis of HNSCC is related to its stage of recurrence and lymph node metastasis. USP7 participates in intracellular tumor regulation, DNA repair, immune response, and epigenetic effects [37]. An immunohistochemical study showed that USP7 overexpression is correlated with histone-lysine N-methyltransferase (EZH2) in HNSCC [16]. EZH2 can promote the epithelial-mesenchymal transformation (EMT) in vivo and inhibits cellular senescence and differentiation [38]. EZH2 is widely expressed in various malignant tumors, including nasopharyngeal carcinoma [39]. USP7 expression in poorly differentiated HNSCC is higher than that in well differentiated HNSCC, and the high expression of USP7 was significantly related to a high degree of lymphatic invasion and high TNM stage. Survival analysis showed that USP7 overexpression is correlated with poor prognosis in HNSCC patients [16].
USP2a is one of the two splicing variants of USP2, which regulates the stability and function of many important cell growth and differentiation regulators and signal transduction factors in vivo [40]. In HNSCC, increased USP2a is associated with poor prognosis. The expression of ErbB2-interacting protein (Erbin) and USP2a increased in HNSCC, indicating that the expression of Erbin and USP2a was positively correlated with lymph node metastasis. Moreover, USP2a expression is related to epidermal growth factor (EGF) in HNSCC [41].

4. The Role of Deubiquitinating Enzymes in Radiosensitivity of Head and Neck Squamous Cell Carcinoma 

For the patients with HNSCC in the advanced stage, surgery combined with radiotherapy is needed to improve the survival rate of the patients. The radiation target and dose should be determined according to the location of the primary tumor, clinical-stage, postoperative pathological diagnosis, and postoperative imaging evaluation. The tolerance of HNSCC to radiotherapy is the main factor affecting the prognosis. BRCA1-associated protein-1 (BAP1), also known as UCHL2 can regulate various cellular processes including cell cycle, cell differentiation, transcription, DNA damage response, and resistance to tumor radiotherapy. BAP1 mutation can increase the sensitivity of HNSCC to radiotherapy and lead to tumor susceptibility syndrome, which is not related to the status of high-risk human papillomavirus (HPV) and p53 tumor suppressor protein. It was found that the survival fraction of BAP1 knockout HNSCC was significantly lower than that of HNSCC cells after radiotherapy, the sensitivity to radiotherapy was increased, and this sensitivity could be reversed by forced re-expression [22]. BAP1 can enhance the stability of histone H2A by deubiquitination and increase its expression level, thus interfering with the modification of chromatin and histone at the double strand break, reducing the rate of cell proliferation and increasing the sensitivity of radiotherapy [42]. HNSCC that is driven by HPV is more sensitive to DNA-damaging therapy than HPV-negative HNSCC. A recent study revealed that p16, the clinically used surrogate for HPV positivity, renders cells more sensitive to radiotherapy via the p16–HUWE1–USP7–TRIP12 pathway [43].

5. The Role of Deubiquitinating Enzymes in Immune Mechanisms of Head and Neck Squamous Cell Carcinoma 

Cancer is considered to be an immunosuppressive disease that is characterized by dysfunction of immune cells and disturbance of cytokine excretion [44]. EBV is closely related to the occurrence of HNSCC [45]. BPLF1 is the largest protein in EBV. There is deubiquitinating activity in the first 205 amino acids of EBV proteins. Its deubiquitinating activity can cleave K63 and K48 polyubiquitin chains. These two regulatory functions play a role in preventing virus protein degradation [46]. When the BPLF1 of EBV was knocked out, When the BPLF1 of EBV was knocked out, the replication quantity and infectivity of its genome decreased. The BPLF1 protein of EBV and its conserved deubiquitinating activity regulate cellular DNA repair enzyme polymerase and recruit it to potential virus destruction and replication sites, thus enhancing the ability to produce infectious viruses. BPLF1 can increase the fault tolerance rate of EBV virus after infecting human DNA by deubiquitinating and stabilizing EBV virus polymerase Pol, so that the DNA of the virus can continue to replicate in the injured site, thus increasing the infectivity of the virus [47]. It has been found that BPLF1 inhibits NF-κB signal transduction during lysozyme infection via deubiquitinating TNF receptor-related factor 6 (TRAF6) [48]. As HNSCC is closely related to EBV infection, the existence of BPLF1 may promote the HNSCC development.
USP9X upregulation can lead to programmed death receptor-ligand 1 (PD-L1) deubiquitination and PD-L1 stable expression in HNSCC tissues. PD-L1 inhibits T-cell activation and proliferation and allows cancer cells to escape T-cell immune surveillance. Preventing USP9X from locating PD-L1 may be an effective strategy for the treatment of HNSCC, especially metastatic tumors [19].
The conserved cylindromatosis (CYLD) belongs to the family of USPs, and its deletion can activate NF-κB and MAPK signaling pathways in HNSCC. NF-κB transcription factors can promote cell survival and induce innate and adaptive immunity to pathogens, such as viruses or bacterial pathogens, inflammatory cytokines, which are abnormally activated during the occurrence, and the development of cancer. The main target of CYLD is the classical NF-κB signal transduction that is mediated by NF-κB essential regulatory protein (NEMO) and cytokine reactive IκB kinase (IKK) complex subunit IKK-γ. CYLD deubiquitinates NEMO and prevents the phosphorylation of IκB and NF-κB activation [49]. The loss of CYLD in HNSCC can also increase the invasiveness of HNSCC by promoting transforming growth factor beta receptor 1 (ALK5) to stabilize NF-κB.

6. The Therapeutic Effect of Deubiquitinating Enzymes on Head and Neck Squamous Cell Carcinoma

As DUBs have become a clinical target for tumor treatment, many people are paying more and more attention to the application of DUBs targeting drugs in cancer therapy. As most ubiquitin enzymes are cysteinases, it is easier to develop into a candidate drug. The effects of DUB inhibitors are as follows: (1) to increase the aggregation of polyubiquitin molecules, (2) to reduce the mono-ubiquitin part, and (3) to change some molecular activities, especially the persistence of carcinogenic proteins that are mediated by DUBs [50]. The inhibition of DUBs can lead to functional impairment of the proteasome and the accumulation of misfolded proteins, resulting in tumor cytotoxicity and death [51]. Some DUBs are associated with cancer and can be used as targets for new inhibitors [52][53]. At present, by screening the DUB inhibitor library, it was found that compound 2X-0324 had a potential radio-sensitizing effect on laryngeal cancer (RER > 1–1.86). Vif1 and Vif2 are protease inhibitors of USP7, which can regulate the anticancer effect that is mediated by p53 and have the potential to become molecular targeted drugs for the treatment of laryngeal carcinoma [54]. Azepan-4-ones and b-AP15 are protease inhibitors of USP14 and UCHL5. They can induce the accumulation of high molecular weight polyubiquitin proteins, resulting in the enhancement of the unfolded protein response (UPR). Both can inhibit the development of HNSCC [55]. In tongue cancer, b-AP15 can significantly inhibit the growth of tumor cells and increase apoptosis in a dose-dependent manner, thereby overcoming the drug resistance of bortezomib in vitro [56].
Squamous cell carcinoma of the head and neck is the most common malignant tumor of the head and neck, and its occurrence and development are related to a variety of DUBdeubiquitination enzymes [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Some DUBs are not only functional in head and neck squamous cell carcinomas but are also important in other squamous cell carcinomas. For example, CYLD is associated with HPV infection and inhibits NF-κB signaling in HNSCC, further promoting the growth and metastasis of head and neck cancer. The same functions of CYLD and HPV occur in cervical cancer cells [57]. In addition, USP46 is also associated with HPV infection in esophageal squamous cell carcinoma, but it has not been reported in HNSCC [58]. The Hippo/YAP signaling pathway plays an important role in HNSCC [59]. USP36 promotes proliferation and invasion of esophageal squamous cell carcinoma by deubiquitination of YAP [60]. USP36 may also play an important role in head and neck cancer.

This entry is adapted from the peer-reviewed paper 10.3390/ijms24010552

References

  1. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424.
  2. Argiris, A.; Karamouzis, M.V.; Raben, D.; Ferris, R.L. Head and neck cancer. Lancet 2008, 371, 1695–1709.
  3. Pezzuto, F.; Buonaguro, L.; Caponigro, F.; Ionna, F.; Starita, N.; Annunziata, C.; Buonaguro, F.M.; Tornesello, M.L. Update on Head and Neck Cancer: Current Knowledge on Epidemiology, Risk Factors, Molecular Features and Novel Therapies. Oncology 2015, 89, 125–136.
  4. Morgan, E.L.; Chen, Z.; Van Waes, C. Regulation of NFkappaB Signalling by Ubiquitination: A Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma? Cancers 2020, 12, 2877.
  5. Shinriki, S.; Jono, H.; Maeshiro, M.; Nakamura, T.; Guo, J.; Li, J.D.; Ueda, M.; Yoshida, R.; Shinohara, M.; Nakayama, H.; et al. Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma. J. Pathol. 2018, 244, 367–379.
  6. Liu, S.; de Boeck, M.; van Dam, H.; Ten Dijke, P. Regulation of the TGF-beta pathway by deubiquitinases in cancer. Int. J. Biochem. Cell Biol. 2016, 76, 135–145.
  7. Zheng, N.; Chu, M.; Lin, M.; He, Y.; Wang, Z. USP7 stabilizes EZH2 and enhances cancer malignant progression. Am. J. Cancer Res. 2020, 10, 299–313.
  8. Sacco, J.J.; Coulson, J.M.; Clague, M.J.; Urbe, S. Emerging roles of deubiquitinases in cancer-associated pathways. IUBMB Life 2010, 62, 140–157.
  9. Gatti, V.; Bernassola, F.; Talora, C.; Melino, G.; Peschiaroli, A. The Impact of the Ubiquitin System in the Pathogenesis of Squamous Cell Carcinomas. Cancers 2020, 12, 1595.
  10. Prieto-Garcia, C.; Hartmann, O.; Reissland, M.; Braun, F.; Fischer, T.; Walz, S.; Schulein-Volk, C.; Eilers, U.; Ade, C.P.; Calzado, M.A.; et al. Maintaining protein stability of ∆Np63 via USP28 is required by squamous cancer cells. EMBO Mol. Med. 2020, 12, e11101.
  11. Prieto-Garcia, C.; Tomaskovic, I.; Shah, V.J.; Dikic, I.; Diefenbacher, M. USP28: Oncogene or Tumor Suppressor? A Unifying Paradigm for Squamous Cell Carcinoma. Cells 2021, 10, 2652.
  12. Jing, C.; Duan, Y.; Zhou, M.; Yue, K.; Zhuo, S.; Li, X.; Liu, D.; Ye, B.; Lai, Q.; Li, L.; et al. Blockade of deubiquitinating enzyme PSMD14 overcomes chemoresistance in head and neck squamous cell carcinoma by antagonizing E2F1/Akt/SOX2-mediated stemness. Theranostics 2021, 11, 2655–2669.
  13. Zhang, S.; Yu, S.; Wang, J.; Cheng, Z. Identification of PSMD7 as a prognostic factor correlated with immune infiltration in head and neck squamous cell carcinoma. Biosci. Rep. 2021, 41, BSR20203829.
  14. Goncharov, T.; Niessen, K.; de Almagro, M.C.; Izrael-Tomasevic, A.; Fedorova, A.V.; Varfolomeev, E.; Arnott, D.; Deshayes, K.; Kirkpatrick, D.S.; Vucic, D. OTUB1 modulates c-IAP1 stability to regulate signalling pathways. EMBO J. 2013, 32, 1103–1114.
  15. Ge, W.L.; Xu, J.F.; Hu, J. Regulation of Oral Squamous Cell Carcinoma Proliferation Through Crosstalk Between SMAD7 and CYLD. Cell Physiol. Biochem. 2016, 38, 1209–1217.
  16. Zhang, M.J.; Chen, D.S.; Li, H.; Liu, W.W.; Han, G.Y.; Han, Y.F. Clinical significance of USP7 and EZH2 in predicting prognosis of laryngeal squamous cell carcinoma and their possible functional mechanism. Int. J. Clin. Exp. Pathol. 2019, 12, 2184–2194.
  17. Xu, L.; Li, Y.Y.; Zhang, Y.C.; Wu, Y.X.; Guo, D.D.; Long, D.; Liu, Z.H. A Novel Ferroptosis-Related Gene Signature to Predict Prognosis in Patients with Head and Neck Squamous Cell Carcinoma. Dis. Markers 2021, 2021, 5759927.
  18. Hou, X.; Wang, L.; Zhang, L.; Pan, X.; Zhao, W. Ubiquitin-specific protease 4 promotes TNF-alpha-induced apoptosis by deubiquitination of RIP1 in head and neck squamous cell carcinoma. FEBS Lett. 2013, 587, 311–316.
  19. Jingjing, W.; Wenzheng, G.; Donghua, W.; Guangyu, H.; Aiping, Z.; Wenjuan, W. Deubiquitination and stabilization of programmed cell death ligand 1 by ubiquitin-specific peptidase 9, X-linked in oral squamous cell carcinoma. Cancer Med. 2018, 7, 4004–4011.
  20. Nanayakkara, D.M.; Nguyen, M.N.; Wood, S.A. Deubiquitylating enzyme, USP9X, regulates proliferation of cells of head and neck cancer lines. Cell Prolif. 2016, 49, 494–502.
  21. Dou, Y.; Lin, J.; Shu, H.; Jiang, N. Role of ubiquitin-specific peptidase 22 in carcinogenesis of human pharyngeal squamous cell carcinoma. Mol. Med. Rep. 2014, 10, 2973–2978.
  22. Liu, X.; Kumar, M.; Yang, L.; Molkentine, D.P.; Valdecanas, D.; Yu, S.; Meyn, R.E.; Heymach, J.V.; Skinner, H.D. BAP1 Is a Novel Target in HPV-Negative Head and Neck Cancer. Clin. Cancer Res. 2018, 24, 600–607.
  23. Glinsky, G.V.; Berezovska, O.; Glinskii, A.B. Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. J. Clin. Investig. 2005, 115, 1503–1521.
  24. Zhang, X.Y.; Varthi, M.; Sykes, S.M.; Phillips, C.; Warzecha, C.; Zhu, W.; Wyce, A.; Thorne, A.W.; Berger, S.L.; McMahon, S.B. The putative cancer stem cell marker USP22 is a subunit of the human SAGA complex required for activated transcription and cell-cycle progression. Mol. Cell 2008, 29, 102–111.
  25. Ling, S.; Li, J.; Shan, Q.; Dai, H.; Lu, D.; Wen, X.; Song, P.; Xie, H.; Zhou, L.; Liu, J.; et al. USP22 mediates the multidrug resistance of hepatocellular carcinoma via the SIRT1/AKT/MRP1 signaling pathway. Mol. Oncol. 2017, 11, 682–695.
  26. Zhuang, Y.J.; Liao, Z.W.; Yu, H.W.; Song, X.L.; Liu, Y.; Shi, X.Y.; Lin, X.D.; Zhou, T.C. ShRNA-mediated silencing of the ubiquitin-specific protease 22 gene restrained cell progression and affected the Akt pathway in nasopharyngeal carcinoma. Cancer Biol. Ther. 2015, 16, 88–96.
  27. Liu, H.; Liu, N.; Zhao, Y.; Zhu, X.; Wang, C.; Liu, Q.; Gao, C.; Zhao, X.; Li, J. Oncogenic USP22 supports gastric cancer growth and metastasis by activating c-Myc/NAMPT/SIRT1-dependent FOXO1 and YAP signaling. Aging (Albany NY) 2019, 11, 9643–9660.
  28. Atanassov, B.S.; Dent, S.Y. USP22 regulates cell proliferation by deubiquitinating the transcriptional regulator FBP1. EMBO Rep. 2011, 12, 924–930.
  29. Liu, W.; Wang, D.; Liu, L.; Wang, L.; Yan, M. miR-140 inhibits osteosarcoma progression by impairing USP22-mediated LSD1 stabilization and promoting p21 expression. Mol. Ther. Nucleic Acids 2021, 24, 436–448.
  30. Liu, T.; Liu, J.; Chen, Q.; Jin, S.; Mi, S.; Shao, W.; Kudo, Y.; Zeng, S.; Qi, G. Expression of USP22 and the chromosomal passenger complex is an indicator of malignant progression in oral squamous cell carcinoma. Oncol. Lett. 2019, 17, 2040–2046.
  31. Tchakarska, G.; Sola, B. The double dealing of cyclin D1. Cell Cycle 2020, 19, 163–178.
  32. Wang, M.L.; Panasyuk, G.; Gwalter, J.; Nemazanyy, I.; Fenton, T.; Filonenko, V.; Gout, I. Regulation of ribosomal protein S6 kinases by ubiquitination. Biochem. Biophys Res. Commun. 2008, 369, 382–387.
  33. Schwickart, M.; Huang, X.; Lill, J.R.; Liu, J.; Ferrando, R.; French, D.M.; Maecker, H.; O’Rourke, K.; Bazan, F.; Eastham-Anderson, J.; et al. Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature 2010, 463, 103–107.
  34. Panasyuk, G.; Nemazanyy, I.; Filonenko, V.; Gout, I. Ribosomal protein S6 kinase 1 interacts with and is ubiquitinated by ubiquitin ligase ROC1. Biochem. Biophys Res. Commun. 2008, 369, 339–343.
  35. Khan, O.M.; Carvalho, J.; Spencer-Dene, B.; Mitter, R.; Frith, D.; Snijders, A.P.; Wood, S.A.; Behrens, A. The deubiquitinase USP9X regulates FBW7 stability and suppresses colorectal cancer. J. Clin. Investig. 2018, 128, 1326–1337.
  36. Chen, X.; Wu, J.; Chen, Y.; Ye, D.; Lei, H.; Xu, H.; Yang, L.; Wu, Y.; Gu, W. Ubiquitin-specific protease 14 regulates cell proliferation and apoptosis in oral squamous cell carcinoma. Int. J. Biochem. Cell Biol. 2016, 79, 350–359.
  37. Nicholson, B.; Suresh Kumar, K.G. The multifaceted roles of USP7: New therapeutic opportunities. Cell Biochem. Biophys. 2011, 60, 61–68.
  38. Yamagishi, M.; Uchimaru, K. Targeting EZH2 in cancer therapy. Curr. Opin. Oncol. 2017, 29, 375–381.
  39. Tong, Z.T.; Cai, M.Y.; Wang, X.G.; Kong, L.L.; Mai, S.J.; Liu, Y.H.; Zhang, H.B.; Liao, Y.J.; Zheng, F.; Zhu, W.; et al. EZH2 supports nasopharyngeal carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1/HDAC2 and Snail to inhibit E-cadherin. Oncogene 2012, 31, 583–594.
  40. Kim, J.; Kim, W.J.; Liu, Z.; Loda, M.; Freeman, M.R. The ubiquitin-specific protease USP2a enhances tumor progression by targeting cyclin A1 in bladder cancer. Cell Cycle 2012, 11, 1123–1130.
  41. da Silva, S.D.; Cunha, I.W.; Nishimoto, I.N.; Soares, F.A.; Carraro, D.M.; Kowalski, L.P.; Graner, E. Clinicopathological significance of ubiquitin-specific protease 2a (USP2a), fatty acid synthase (FASN), and ErbB2 expression in oral squamous cell carcinomas. Oral. Oncol. 2009, 45, e134–e139.
  42. Yu, H.; Pak, H.; Hammond-Martel, I.; Ghram, M.; Rodrigue, A.; Daou, S.; Barbour, H.; Corbeil, L.; Hebert, J.; Drobetsky, E.; et al. Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair. Proc. Natl. Acad. Sci. USA 2014, 111, 285–290.
  43. Molkentine, D.P.; Molkentine, J.M.; Bridges, K.A.; Valdecanas, D.R.; Dhawan, A.; Bahri, R.; Hefner, A.J.; Kumar, M.; Yang, L.; Abdelhakiem, M.; et al. p16 Represses DNA Damage Repair via a Novel Ubiquitin-Dependent Signaling Cascade. Cancer Res. 2022, 82, 916–928.
  44. Varilla, V.; Atienza, J.; Dasanu, C.A. Immune alterations and immunotherapy prospects in head and neck cancer. Expert Opin. Biol. Ther. 2013, 13, 1241–1256.
  45. Klatka, J.; Hymos, A.; Szkatula-Lupina, A.; Grywalska, E.; Klatka, B.; Terpilowski, M.; Stepulak, A. T-Lymphocyte Activation Is Correlated With the Presence of Anti-EBV in Patients With Laryngeal Squamous Cell Carcinoma. In Vivo 2019, 33, 2007–2012.
  46. Whitehurst, C.B.; Ning, S.; Bentz, G.L.; Dufour, F.; Gershburg, E.; Shackelford, J.; Langelier, Y.; Pagano, J.S. The Epstein-Barr virus (EBV) deubiquitinating enzyme BPLF1 reduces EBV ribonucleotide reductase activity. J. Virol. 2009, 83, 4345–4353.
  47. Dyson, O.F.; Pagano, J.S.; Whitehurst, C.B. The Translesion Polymerase Pol eta Is Required for Efficient Epstein-Barr Virus Infectivity and Is Regulated by the Viral Deubiquitinating Enzyme BPLF1. J. Virol. 2017, 91, e00600-17.
  48. Saito, S.; Murata, T.; Kanda, T.; Isomura, H.; Narita, Y.; Sugimoto, A.; Kawashima, D.; Tsurumi, T. Epstein-Barr virus deubiquitinase downregulates TRAF6-mediated NF-kappaB signaling during productive replication. J. Virol. 2013, 87, 4060–4070.
  49. DiDonato, J.A.; Mercurio, F.; Karin, M. NF-kappaB and the link between inflammation and cancer. Immunol. Rev. 2012, 246, 379–400.
  50. D’Arcy, P.; Wang, X.; Linder, S. Deubiquitinase inhibition as a cancer therapeutic strategy. Pharmacol. Ther. 2015, 147, 32–54.
  51. Poondla, N.; Chandrasekaran, A.P.; Kim, K.S.; Ramakrishna, S. Deubiquitinating enzymes as cancer biomarkers: New therapeutic opportunities? BMB Rep. 2019, 52, 181–189.
  52. Singh, N.; Singh, A.B. Deubiquitinases and cancer: A snapshot. Crit. Rev. Oncol. Hematol. 2016, 103, 22–26.
  53. Mofers, A.; Pellegrini, P.; Linder, S.; D’Arcy, P. Proteasome-associated deubiquitinases and cancer. Cancer Metastasis Rev. 2017, 36, 635–653.
  54. Lee, H.R.; Choi, W.C.; Lee, S.; Hwang, J.; Hwang, E.; Guchhait, K.; Haas, J.; Toth, Z.; Jeon, Y.H.; Oh, T.K.; et al. Bilateral inhibition of HAUSP deubiquitinase by a viral interferon regulatory factor protein. Nat. Struct. Mol. Biol. 2011, 18, 1336–1344.
  55. Tian, Z.; D’Arcy, P.; Wang, X.; Ray, A.; Tai, Y.T.; Hu, Y.; Carrasco, R.D.; Richardson, P.; Linder, S.; Chauhan, D.; et al. A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance. Blood 2014, 123, 706–716.
  56. Woo, R.A.; Jack, M.T.; Xu, Y.; Burma, S.; Chen, D.J.; Lee, P.W. DNA damage-induced apoptosis requires the DNA-dependent protein kinase, and is mediated by the latent population of p53. EMBO J. 2002, 21, 3000–3008.
  57. An, J.; Mo, D.; Liu, H.; Veena, M.S.; Srivatsan, E.S.; Massoumi, R.; Rettig, M.B. Inactivation of the CYLD deubiquitinase by HPV E6 mediates hypoxia-induced NF-kappaB activation. Cancer Cell. 2008, 14, 394–407.
  58. Kiran, S.; Dar, A.; Singh, S.K.; Lee, K.Y.; Dutta, A. The Deubiquitinase USP46 Is Essential for Proliferation and Tumor Growth of HPV-Transformed Cancers. Mol. Cell 2018, 72, 823–835.e5.
  59. Shin, E.; Kim, J. The potential role of YAP in head and neck squamous cell carcinoma. Exp. Mol. Med. 2020, 52, 1264–1274.
  60. Zhang, W.; Luo, J.; Xiao, Z.; Zang, Y.; Li, X.; Zhou, Y.; Zhou, J.; Tian, Z.; Zhu, J.; Zhao, X. USP36 facilitates esophageal squamous carcinoma progression via stabilizing YAP. Cell Death Dis. 2022, 13, 1021.
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