JOSD1 promotes proliferation and chemoresistance of head and neck squamous cell carcinoma under the epigenetic regulation of BRD4

Abstract

Background Deubiquitinating enzymes (DUBs) play critical roles in various cancers by modulating functional proteins post-translationally. Previous studies have demonstrated that DUB Josephin Domain Containing 1 (JOSD1) is implicated in tumor progression, however, the role and mechanism of JOSD1 in head and neck squamous cell carcinoma (HNSCC) remain to be explored. In this study, we aimed to identify the clinical significance and function of JOSD1 in HNSCC. Methods The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were analyzed to find novel DUBs in HNSCC. Immunohistochemistry assay was performed to determine the expression of JOSD1 in our cohort of 42 patients suffered with HNSCC. Kaplan–Meier analysis was used to identify the correlation between JOSD1 and the prognosis of HNSCC patients. The regulation of BRD4 on JOSD1 was determined by using pharmacological inhibition and gene depletion. The in vitro and in vivo experiments were conducted to elucidate the role of JOSD1 in HNSCC. Results The results of IHC showed that JOSD1 was aberrantly expressed in HNSCC specimens, especially in the chemoresistant ones. The overexpression of JOSD1 indicated poor clinical outcome of HNSCC patients. Moreover, JOSD1 depletion dramatically impaired cell proliferation and colony formation, and promoted cisplatin-induced apoptosis of HNSCC cells in vitro. Additionally, JOSD1 suppression inhibited the tumor growth and improved chemosensitivity in vivo. The epigenetic regulator BRD4 contributed to the upregulation of JOSD1 in HNSCC. Conclusions These results demonstrate that JOSD1 functions as an oncogene in HNSCC progression, and provide a promising target for clinical diagnosis and therapy of HNSCC.

MJDs family members: Potential prognostic targets and immune-associated biomarkers in hepatocellular carcinoma

“…ATXN3L directly interacted with KLF5, thus, reducing KLF5's ubiquitination and degradation (Ge et al, 2015). JOSD1 was found to be up-regulated in the head and neck squamous cell carcinoma (HNSCC) (Jing et al, 2021), gynaecological cancer (GC) cells (Wu et al, 2020), and acute myeloid leukemia (AML) cells (Yang et al, 2022). Overexpressed JOSD2 was positively correlated with the worse prognosis in hepatocellular carcinoma (Huang et al, 2022), cholangiocarcinoma (CCA) (Qian et al, 2021), and NSCLC (Krassikova et al, 2021).…”

Mitochondria, mitophagy, and the role of deubiquitinases as novel therapeutic targets in liver pathology

“…In contrast, JOSD1 depletion reduced cell proliferation and colony formation, and promoted cisplatin‐induced apoptosis of HNSCC cells in vitro. Additionally, JOSD1 suppression inhibited the tumor growth and improved chemosensitivity against cisplatin in a xenograft mouse model 63 …”

“…Additionally, JOSD1 suppression inhibited the tumor growth and improved chemosensitivity against cisplatin in a xenograft mouse model. 63 Together, these aspects defined above may also be relevant for HCC or hepatocellular functions in general, but direct proof is currently missing.…”

“…Additionally, JOSD1 suppression inhibited the tumor growth and improved chemosensitivity against cisplatin in a xenograft mouse model. 63 …”

BRD4 regulates the induction and maintenance of cancer stem cells in squamous cell carcinoma

“…Further investigation into the role of BRD4 in skin SCCs showed that it is required for the expression of cyclin D1, BCL-2 and MYC oncogenes (14). Similar studies have also shown that BRD4 collaborates with YAP1 (15) or JOSD1 (16) to promote the tumorigenesis of head and neck squamous cell carcinoma (HNSCC). Therefore, BRD4 is broadly recognized as an important therapeutic target in SCC; the fact that over 30 targeted inhibitors of various BET family members including BRD4 are currently in preclinical and clinical trials is testament to its perceived importance.…”