Oral squamous cell carcinoma (OSCC) is a type of cancer affecting the head and neck, which currently stands as the foremost cause of cancer-related deaths globally. The development of OSCC is frequently linked to various risk factors, including but not limited to smoking, alcohol consumption, chewing habits, and infection with high-risk human papillomavirus [1, 2]. Although surgical procedures, radiation therapy, and chemotherapy have demonstrated significant advantages, the potential for cancer recurrence following treatment may be increased by drug resistance and severe side effects. Therefore, the search for effective and safe drugs is critical. Natural compounds, due to their safety, have recently become a focal point in the quest for anti-cancer drugs as potential alternatives [3].
Aberration of chromatin modifications of histone tails leads to carcinogenesis [4]. Jumonji C domains protein families have been identified as major contributors to various human cancers via epigenetic remodeling [5, 6]. Jumonji-C domain-containing protein 5 (JMJD5), renamed KDM8, is involved in, embryonic development [7], the metabolic regulator [8], osteoclastogenesis [9], circadian rhythm regulation [10], and tumorigenesis [11]. Although the specific ways in which KDM8 contributes to the advancement of cancer are not fully understood, it is hypothesized that its role as a histone demethylase could be significant in controlling the expression of crucial genes implicated in tumorigenesis [4]. KDM8 is highly expressed in various types of cancer such as breast, lung, stomach, prostate, colon, and oral cancers [11–18]. The upregulation of KDM8 in these cancers has been linked with enhanced cell proliferation, migration, and invasion, which indicates its involvement in tumor progression. Additionally, KDM8 can regulate the nuclear translocation of pyruvate kinase muscle isozyme (PKM2) and alter HIF-1alpha-mediated glucose metabolism [8]. In addition, KDM8 functions as a histone demethylase that specifically removes methyl groups from lysine 36 on histone H3 (H3K36), resulting in the modulation of gene expression. H3K36 methylation is frequently linked with gene activation, and KDM8 has been demonstrated to control genes involved in the cell cycle [4]. KDM8 is also an H3K36me2 histone demethylase that is revealed positively regulate CCNA1 to regulate cancer cell proliferation [4]. The CCNA1 protein functions as a regulatory subunit for cyclin-dependent kinases (CDKs) in the eukaryotic cell cycle. CDK2 is activated by CCNA1 through specific binding, resulting in the phosphorylation of multiple target proteins that facilitate progression through the G1/S and G2/M phases of the cell cycle [19–21]. Furthermore, a research study found that the inhibition of KDM8 can impede metastasis and prompt apoptosis in oral squamous cell carcinoma through regulation of the p53/NF-κB pathway [11]. KDM8 and CCNA1 may have a function in the regulation of the p53 pathway and affect cell cycle progression and DNA damage responses by interacting with p53. Considering these discoveries, KDM8 is a potential target for cancer treatment. In preclinical models, the inhibition of KDM8 activity has been demonstrated to promote programmed cell death in cancer cells and decrease tumor growth [11, 18].
Previous research has shown that natural compounds derived from plants possess chemopreventive, anticancer, and antimetastatic properties and functions [22]. Isothiocyanates (ITCs) are well-established and have been reported to exhibit anticancer effects in human cancers [23–25]. These compounds are present in a variety of cruciferous vegetables, including cauliflower, brussels sprouts, kale, cabbage, horseradish, and wasabi [25, 26]. Allyl isothiocyanate (AITC; 3-isothiocyanato-1-propene, CH2CHCH2NCS) is responsible for the pungent flavor of mustard, horseradish, radish, and wasabi. AITC, which is a sulfur-containing organic compound, is a product of enzymatic hydrolysis of the glucosinolate sinigrin. Research has shown that AITC can hinder cancer cell progression by impeding cell growth, proliferation, migration, and invasion [25, 26]. AITC has been found to regulate DNA methylation, a process that involves the addition of a methyl group to the DNA molecule, and can reduce DNA methylation in cancer cells. This leads to the reactivation of tumor suppressor genes and inhibition of cancer cell growth [27–31]. AITC has also been found to inhibit the activity of histone deacetylases (HDACs), enzymes involved in regulating histone modification [28, 32, 33]. By inhibiting HDAC activity, AITC can increase histone acetylation, alter gene expression, and prevent cancer cell growth [28]. Furthermore, AITC has been shown to induce apoptosis and G2/M phase arrest in human brain malignant glioma GBM 8401 cells [34] as well as apoptotic death in human cisplatin-resistant oral cancer cells [23]. While AITC has been found to repress tumor cell proliferation in various cancer cell lines, including brain, lung, breast, colorectal, bladder, and cervical cancer cell lines [35–37], there is limited research addressing the AITC-mediated effects on OSCC.
Patient-derived tumor xenograft (PDTX) is one of the most promising platforms for simulating human cancer and its complexity. The histopathology of PDTX tumors is very similar to the histopathology of donor lesions. A large amount of evidence, including mutation status, transcriptome, histology, polymorphism, and copy number variation with high fidelity, also supports the view that the PDTX model is very similar to human tumors’ pathophysiology than the traditional cancer-derived xenograft model [38, 39].
In our previous report, we demonstrated a correlation between the high expression of KDM8 and unfavorable prognosis in OSCC [18]. The present study aimed to explore whether AITC, an epigenetic regulator, can modulate KDM8 and potentially regulate gene expression. This modulation could ultimately inhibit oral cancer cell growth in vitro, in vivo, and in PDTX models.