Oral diseases rank highly amongst widespread health conditions worldwide, and impose notable health and economic burdens, which substantially diminish the quality of life of patients, impacting overall health and well-being (1). Oral cancer is a generic term used to refer to malignant tumors in oral organs. Notably, oral cancer encompasses cancer types of the lip, and all subsites of the oral cavity and oropharynx (2). According to the Global Cancer Statistics 2022, oral cancer was the 16th most common malignancy and the 15th leading cause of mortality worldwide (3), which was similar to the rankings observed in 2018 (4). The incidence of oral cancer is 2.72 cases per 100,000 individuals in China (men, 3.87; women, 1.60). Notably, the aforementioned rate is lower compared with the global incidence rate (men, 5.8; women, 2.3) (3,5). Oral squamous cell carcinoma (OSCC) is the most prevalent and extensively researched type of oral cancer, and the predominant malignancy within the head and neck region (6,7). In China, a total of 65,400 new cases of oral and pharyngeal cancer occurred in 2022 (5). The prevalence of oral cancer is projected to increase by ~40% by 2040 and this may lead to an increase in mortality rates in the future (5). Thus, numerous studies have focused on the molecular mechanisms underlying tumor growth, invasion, migration and distant metastasis, with the aim of identifying novel therapeutic targets and key tumor markers in OSCC. Previous studies have demonstrated that deubiquitinating enzymes (DUBs) serve an important role in the development of OSCC (8,9). The present review aims to investigate the functional mechanisms, tumorigenic regulation and therapeutic targets of DUBs in OSCC, which may provide a novel theoretical basis for the diagnosis and treatment of oral cancer in the future.

In total, ~90% of oral cancer types originate in the stratified non-keratinized epithelium of the oral mucosa (10). Notably, oral cancer may be caused by genetic, epigenetic and environmental factors, including tobacco, alcohol and poor nutrition, which lead to changes in oral keratinocytessize and shape (10). Early genetic and molecular alterations of oral keratinocytes occur in all tissue areas exposed to carcinogens, followed by varying degrees of damage to the epithelium, which may lead to oral epithelial carcinoma and metastasis (Fig. 1) (11). A previous study has demonstrated that the development of OSCC may also be caused by additional factors, such as autoimmune diseases, infectious diseases, immunosuppressive disorders and familial cancer syndromes that modulate the immune system (12).

The key characteristics of oral cancer include sustained cellular proliferation, resistance to apoptosis, invasion and metastasis, dysregulation of energy homeostasis, evasion of growth inhibitory signals, and the ability to circumvent immunotherapeutic interventions (13). Oral carcinogenesis is complex and multifactorial, involving genetic mutations, epigenetic modifications and imbalances in the tumor microenvironment (TME). Genetic alterations may lead to the abnormal activation of oncogenic signaling pathways, including PI3K/AKT/mTOR (14,15), EGFR (16), Wnt/β-catenin (17), Notch (18) and JAK/STAT (19) pathways, and simultaneously disrupt tumor suppressor pathways, such as the tumour protein 53/retinoblastoma pathway (20). Notably, the aforementioned alterations serve a key role in the progression of OSCC. Furthermore, epigenetic modifications, such as DNA methylation (21), histone covalent modifications (22) and chromatin remodeling (23), are also implicated in the initiation and progression of OSCC. Additional factors such as immune suppression (24), hypoxia (25) and imbalances in the oral microbiome (26) may also contribute to the dysregulated TME, thus facilitating OSCC progression.

In clinical practice, patients with OSCC may present with early-stage lesions that are painless. However, as OSCC progresses, lesions may cause ulceration, nodules and tissue adherence (27). In total, ~50% of OSCC cases arise in the posterior lateral border of the tongue, with the remaining cases affecting the floor of the mouth, soft palate, gingiva, buccal mucosa and hard palate (28). Oral cancer is detected in clinical examinations; however, >50% of patients with OSCC are diagnosed during the advanced stages of the disease (stages III and IV) and >40% of patients with OSCC present with regional metastases at the time of diagnosis (28). Furthermore, OSCC may invade the ipsilateral cervical lymph nodes through lymphatic outflow or invade the contralateral or bilateral lymph nodes. Notably, the lungs, bones and liver are the main sites of OSCC metastasis (29).

At present, surgery is the primary treatment option for OSCC; however, adequate resection margins are difficult to achieve due to the complex anatomy of the affected area (13). Ionizing radiation (IR), immunotherapy and chemotherapy may be used to prevent or treat OSCC (13). Thus, the identification of novel biomarkers and therapeutic targets in OSCC is necessary. A recent systematic review has summarized the hallmarks of oral cancer and highlighted the importance of further studies focused on OSCC (30). In addition, numerous mono-antibodies or small molecular compounds that inhibit tumorigenesis have been developed. PRI-724, a specific inhibitor of the Wnt/β-catenin signaling pathway, works synergistically with vismodegib, erlotinib and HS-173 to effectively decrease cell viability, promote apoptosis and decrease cell migration in OSCC (31). Cetuximab, an EGFR-targeting antibody, may be used to enhance the antitumor function of PI3K/AKT inhibitors (32). Current research on oral cancer focuses on the role of DUBs, which exhibit potential as molecular targets in the treatment of oral cancer (8,9).

The sequential enzymatic processes that covalently attach ubiquitin, a 76-residue polypeptide with a molecular mass of ~8.5 kDa, to target proteins, are known as ubiquitylation. Ubiquitylation is achieved through a mechanism that involves several factors, including ubiquitin-activating enzyme (E1), ubiquitin-binding enzyme (E2) and ubiquitin ligase (E3). In humans, there are two variants of E1 enzymes, namely, ubiquitin-like modifier activating enzyme 1 and ubiquitin-like modifier activating enzyme 6, alongside ~50 distinct E2 enzymes and ~600 different E3 enzymes. Notably, E3 enzymes are pivotal in the selective identification of target proteins for ubiquitination and operate in a manner that is both spatially and temporally specific (33). Ubiquitin contains seven lysine residues and an N-terminal region that function as a site for ubiquitination, specifically at positions K6, K11, K27, K29, K33, K48, K63 and M1. Ubiquitin chains bind to substrates by linking the glycine residue of ubiquitin to a lysine molecule of ubiquitin (34). Different linkages exhibit different roles for the target substrate. Notably, K48-linked chains represent the most prevalent type of ubiquitin linkage within cellular environments, accounting for >50% of all ubiquitin linkages (33). The primary function of K48-linked chains is to facilitate the targeting of proteins to the proteasome for degradation. By contrast, K63-linked chains, which are the second most abundant type of ubiquitin linkages, exhibit a range of non-degradative functions (33). Ubiquitination serves a key role in numerous pathological conditions, such as neurodegenerative diseases, various cancers, aging and metabolic disorders (35). Alternate atypical ubiquitin modifications, linked through M1, K6, K11, K27, K29 or K33, also exhibit unique functions in substrate modification (36). Variations in the use of ubiquitin lysine residues may lead to the formation of homotypic chains, which are linked exclusively through a single type of residue, or heterotypic and branched chains. The aforementioned processes are exemplified by K63-linear and K48-K11 hybrid polymers, respectively (37).

DUBs are a class of proteases that facilitate the reversal of protein ubiquitination, a critical process for maintaining healthy cellular homeostasis. DUBs are responsible for the removal of ubiquitin from target proteins, which enables the recycling of ubiquitin, mediated by ~100 distinct DUBs (38). Ubiquitin molecules may be conjugated to the N-terminal amino group or lysine residues on other ubiquitin molecules, which results in the formation of ubiquitin chains (39). DUBs possess the ability to dismantle ubiquitin conjugations by cleaving the linkages between ubiquitin molecules or processing ubiquitin precursors to produce free pools of ubiquitin (Fig. 2A) (39). In total, there are ~100 DUBs that are classified into eight different families, namely, ubiquitin specific protease (USP), ubiquitin carboxy-terminal hydrolase, JAB1/MPN/MOV34 metalloenzyme, ovarian tumor protease (OTU), motif interacting with ubiquitin-containing novel DUB, monocyte chemotactic protein-induced proteins zinc finger-containing ubiquitin peptidase 1 and Machado-Joseph disease (Fig. 2B) (40,41). Furthermore, DUBs exhibit four distinct mechanisms of action, namely, processing of ubiquitin precursors, recycling of ubiquitin molecules during ubiquitination, cleavage of poly-ubiquitin chains and reversal of ubiquitin conjugation (42). The aforementioned mechanisms are used to regulate several cellular functions, including cell cycle progression, vesicle transport, signal transduction and chromosome segregation (43). DUBs also serve key roles in various developmental processes of eukaryotic cells, including apoptosis (44), DNA damage repair (45), maintenance of cell stemness (46) and tumorigenesis (47). Thus, the association between ubiquitination and DUBs is essential for cellular homeostasis.

Numerous DUBs may be associated with either tumor-suppressive or oncogenic activities and exhibit potential as candidates for therapeutic intervention. Table I highlights key studies that focus on the regulatory mechanisms of DUBs in oral cancer under reference summarized.

Aberrant activation and expression of signaling pathway components are commonly observed in OSCC, which may promote tumor cell proliferation, invasion and metastasis, and inhibit apoptosis (82). Regulation of DUBs in OSCC is considered to be an important factor in the abnormal activation of signaling pathways (83–89). Notably, DUBs operate through four distinct mechanisms: i) The processing of ubiquitin protein precursors; ii) the retrieval of ubiquitin molecules during the ubiquitination process; iii) the cleavage of ubiquitin protein chains; and iv) the disassociation of ubiquitin proteins from substrate targets. According to the aforementioned functions, DUBs may reverse the ubiquitination of target proteins, thereby contributing to the equilibrium between ubiquitination and deubiquitination of substrate proteins (90). While DUBs are known to be involved in the initiation and progression of OSCC, the specific mechanisms and downstream effects of DUBs remain poorly understood. DUBs have a dual role in oral cancer. The upregulation of some DUBs, such as USP14 and USP9X, promotes tumor development, while the downregulation of others like CYLD is linked to tumor invasion and drug resistance. By regulating key pathways (Wnt/β-catenin, NF-κB, TGF-β and P53), DUBs influence tumor progression. Their expression levels correlate with patient prognosis, suggesting a potential as therapeutic targets. Clinically, DUBs can indicate the prognosis of invasive OSCC patients. Targeting DUBs may overcome treatment resistance, and some DUBs inhibitors might enhance therapeutic effects when combined with other treatments. Given their potential as therapeutic targets in the treatment of OSCC, further research is warranted to elucidate the regulatory mechanisms associated with DUBs and to assess the potential side effects of targeted therapies.