HomeENGLISH MAGAZINEUSP15: from brain inflammation to cancer, the master-zyme tags the repair and...

USP15: from brain inflammation to cancer, the master-zyme tags the repair and shows itself as a target

Ubiquitin is a highly conserved peptide molecule, composed of 76 amino acids that mark proteins for degradation. Protein ubiquitination changes proteins half-life and tightly regulates the levels of proteins that should be erased before they start to put in danger cellular homeostasis. Ubiquitination often affects protein stability, localization, activity, and interactions, and is widely involved in important physiological processes, including cell apoptosis, the cell cycle, ribosome biogenesis, DNA damage repair, stress responses and the induction of inflammatory responses. The ubiquitination process is reversible. The removal of ubiquitin molecules from the ubiquitinated protein, and stabilizing the substrate protein, is known as the deubiquitination process, which requires the involvement of deubiquitinating enzymes (DUBs).  Deubiquitinases play critical roles in ubiquitin-directed signaling by removing the protein “tag” ubiquitin from substrates.

The deubiquitinase USP15 plays an important role in cancer cells’ response to PARP inhibitors (chemodrugs) and more recent researchers indicate that it is involved in multiple aspects of either cellular signaling and, consequently, in human pathology. USP15 is a member of the largest subfamily of cysteine protease DUBs. It has been implicated in the biological effects of trasforming growth factor and one morphogenetic protein response, immune responses, neuro-inflammation and possibily also cancer development. USP15 is upregulated in a variety of cancers, including breast cancer, ovarian cancer, prostate cancer, stomach cancer, multiple myeloma, glioblastoma and pancreatic ductal adenocarcinoma. Ths fact that USP15 gene is deleted in 10% of glioblastomas and 25% of pancreatic cancers leads to think that it might have a potential tumor suppressive function in these contextes.

USP15 promotes the proliferation of the breast cancer cells by deubiquitinating and stabilizing the estrogen receptor α (ERα) in vitro and in vivo, which is related to the cell cycle regulation, rather than cell death. Therefore, USP15 confers growth advantages in hormone-responsive breast tumors. There are many reports that USPs participate in the development of gastric cancer and can be used as independent prognostic markers for patients with this condition. USP15 overexpression also promotes the nuclear expression of β-catenin, thereby activating the Wnt/β-caten in signaling pathway to promote the malignant progression of stomach cancers. As one may see, not all type of cancers benefit for USP15 deletion, as seen for brain cancers or pancreatic carcinoma. USP15 however, but also plays a role in cellular autophagy. Parkinson’s disease is a neurodegeneration whose pathogenesis is mainly due to mitochondrial dysfunction.

The E3 ligase PARKIN is implicated in this disease and it has been reported to play a critical role in the autophagy clearance of defective mitochondria. USP15 can deubiquitinate PARKIN to impair mitochondrial autophagy, suggesting that USP15 inhibition could be a therapeutic strategy for Parkinson’s disease where reduced PARKIN levels are eventually represented. Finally, USP15 has a clear role in genomen integrit and stability. Environemntal insults like ultraviolet and ionizing radioations, heavy metals, and polycyclic compounds are amongst the commonest agetns capable to cause DNA lesions. Cellular oxidative stress is, on the other hand, the major inner responsible for potentially harmful effects on our chromatine. In mammalian cells, there are two prominent repair pathways that repair double strand breaks: the homologous recombination (HR) repair and the non-homologous end-joining (NHEJ) mechanism.

NHEJ is referred to as “non-homologous” because the break ends are directly ligated without homologous templates. So, NHEJ is commonly associated with the presence of insertions and deletions at DNA doubles strand breaks. HR is different from NHEJ, which needs an intact homologous template. USP15 is enrolled by the MDC1 protein onto the DNA double-strand break to deubiquitinate BRCA-like BARD1 enzyme, enhancing the BRCA1/BARD1 retention at the DNA lesion to fulfill the repair. This is a strategy to employ in cancer chemotherapy since the aforementioned mechanism reduces the PARP inhibitor sensitivity in breast and ovarian cancer cells. PARP inhibitors are among the newest and selective weapons currently used against several types of cancer; yet cases of cellular resistance are now being evidenced.

Scientists started to think that one mechanism for cellular esistance against the mis because of the USP15 work of stabilization in the NHEJ repair mechanism. This is why high throughput screenings have benne performed to identify possible USP15 inhibitors to be used in sinergy with PARP inhibitors. Mitoxanthrone, a well known drug used against leukemia and prostate cancer has been found to block USP15 activity by some extent. Almost two years ago, scientists identified the small compound USP15-Inh that showed selectivity against this enzyme compared to other related proteins. There are already proofs that it may kill leukemia cells and good probabilities that it will committed to treat neuroinflammatory disorders, like multiple sclerosis. Proteorex Therapeutics is among the newest companies that are working on this topic.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Li YC, Cai SW et al. Biomedicines. 2022; 10(2):474. 

Georges A et al. Genes Immun 2021; 22(1):12-23.

Niederkorn M, Ishikawa C et al. Leukemia 2021:1–14.

Peng Y et al. Nat Commun. 2019 Mar 15; 10(1):1224.

Teyra J, Singer AU et al. Structure 2019; 27(4):590-605.

Ward SJ et al. J Biol Chem 2018; 293:17362–17374.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica e salute sui siti web salutesicilia.com, medicomunicare.it e in lingua inglese sul sito www.medicomunicare.com
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