Head and neck squamous cell carcinoma (HNSCC) is a malignant tumor with a high incidence in squamous epithelia, such as that of the mouth, maxillofacial and throat, and it is the sixth most common cancer type worldwide [1,2]. GLOBLOCAN data showed that HNSCC accounted for 4.9% of new cancers in 2018, and the age of onset is decreasing [3]. Currently, the most effective early treatment mode remains surgical intervention [4]. However, due to the insidious onset of HNSCC, it is mostly diagnosed in the middle and late stages or after distant metastasis has occurred, and the best treatment time is missed; thus, epidermal growth factor receptor inhibitors (e.g., cetuximab), Taxol and other maintenance treatments are used primarily in the advanced stage ([5,6]). However, the 5-year survival rate of HNSCC patients is still <50 %, which seriously affects the health of patients [7,8]. Therefore, the early diagnosis and treatment of HNSCC still need to be improved, and identifying potential therapeutic targets and molecular mechanisms is important for improving the prognosis of HNSCC patients.

The E3 ubiquitin ligase denticleless E3 ubiquitin protein ligase homolog (DTL), a ubiquitin ligase, enables damage-specific DNA binding protein 1 (DDB1), DDB1 cullin4-associated factor (DCAF), the Cullin protein family member CUL4 A, and the RING finger protein RBX1 to form the cullin 4 A-RING ubiquitin ligase (CRL4A) complex, which catalyzes the direct transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to a lysine residue in the substrate and initiating the ubiquitination process [9,10]). DTL controls the ubiquitin-dependent proteolysis of the substrate in multiple DNA metabolic processes. DTL-degradable DNA-PKcs regulates NHEJ repair and affects genome stability [11]. DTL-mediated degradation of PXD1 prevents PXD1 from interfering with the normal S-phase activity of DNA2[12]. DTL can also be widely involved in tumor progression through the ubiquitination pathway [13]. PDCD4, acting as a ubiquitination substrate of DTL, can regulate the MAPK/JNK pathway to affect the progression of lung cancer [14]). DTL may also contribute to bladder cancer progression through the AKT/mTOR pathway [15]). Exploration of DTL substrates lays the foundation for investigating the mechanism of HNSCC.

Arginine and glutamate rich 1 (ARGLU1) was originally called FLJ10154, and its function is not clear. ARGLU1 overexpression has been found to inhibit the proliferation of gastric cancer cells in vitro and in vivo [16]. Moreover, ARGLU1 can bind to the transcriptional coactivator Mediator 1 (MED1) to regulate estrogen receptor-mediated transcription. ARGLU1 knockdown significantly inhibited the growth and migration of breast cancer cells [17]. However, whether DTL ubiquitinates ARGLU1 to affect the progression of HNSCC needs to be further elucidated.

In this study, we clarified that DTL is upregulated in HNSCC and associated with a poor prognosis. We found that DTL inhibits ARGLU1 expression through K11-linked ubiquitination to regulate the Notch signaling pathway. Furthermore, the correlation of DTL with the proliferation and migration of HNSCC was elucidated. The above studies provide a theoretical basis for the future prevention and treatment of HNSCC.