DNA methylation of metallothionein genes is associated with the clinical features of renal cell carcinoma

Abstract

Metallothioneins are low-weight cysteine-rich proteins responsible for metal ion homeostasis in a cell and, thus, capable of regulating cell proliferation and differentiation. Deregulation of metallothionein genes has been reported in various human tumors. However, their role in renal cell carcinoma (RCC) has been poorly investigated. In the present study, we aimed to evaluate the importance of promoter DNA methylation of selected metallothionein genes for RCC. Based on the initial analysis of kidney renal clear cell carcinoma dataset from The Cancer Genome Atlas, genes MT1E, MT1F, MT1G and MT1M were selected for qualitative methylation analysis in 30 tumors (including 10 multifocal cases), 10 pericancerous, and 30 non-cancerous renal tissues (NRT). Methylation of MT1E and MT1M was tumor-specific (P=0.0056 and P=0.0486, respectively) and showed moderate interfocal variation in paired tumor foci. Methylated promoter status of the two genes was associated with larger tumor size (P=0.0110 and P=0.0156, respectively). Furthermore, aberrant MT1E methylation was more frequent in tumors having necrotic zones (P=0.0449) or characterized with higher differentiation grade (P=0.0144), while MT1M was more commonly methylated in tumors with higher Fuhrman grade (P=0.0272). Only unmethylated MT1F promoter status was observed in all analyzed samples. Gene expression analysis (51 RCC and 9 NRT) revealed MT1G downregulation in tumors (P<0.0001), while lower MT1E expression levels were associated with the promoter methylation (P=0.0077). In clear cell RCC, MT1E, MT1G and MT1M expression was higher than that noted in other histological tumor subtypes (all P<0.0500). In addition, some associations were observed between metabolic syndrome-related clinical parameters and promoter methylation or gene expression. In conclusion, the present study revealed the potential role of MT1E and MT1M promoter methylation in RCC development.

Metallothionein-3 promotes cisplatin chemoresistance remodelling in neuroblastoma

“…These results showed a possible dual role of PDCD10 in drug resistance [52][53][54] . Cellular inactivation of CDDP and subsequent sequestration could be mediated by MTs [55][56][57][58][59] . MTs chelate platinum ions, which prevents their interaction with DNA in Nbl cells, possibly through excretion of metal ions outside the cell.…”

Oxidative stress in genetically triggered thoracic aortic aneurysm: role in pathogenesis and therapeutic opportunities

“…MTs are metal-binding antioxidant proteins with diverse biological functions including heavy metal detoxification, MMP regulation and scavenging of free radicals [51], thus low levels may contribute to MMP-mediated ECM degradation. While inducers of MTs are established and include ROS among other stimuli [51], suppressors of MT expression are less well known [52] but at least include gene silencing by DNA methylation [53]; alternatively, reduced levels might reflect an impaired capacity of damaged cells to induce MT expression [24].…”

Metallothionein isoforms as double agents – Their roles in carcinogenesis, cancer progression and chemoresistance

“…Cisplatin resistance remains a major impediment to the effective treatment of many types of cancers. The cellular inactivation of cisplatin and subsequent sequestration can be mediated by MTs that chelate platinum and prevent interaction with tumor cell DNA (Hou et al, 2017;Maleckaite et al, 2019;Skowron et al, 2018;Wong and Stillman, 2018). In 1997, Hishikawa et al suggested that MT expression in squamous cell carcinoma of the esophagus is a major determinant of cisplatin resistance and may be a predictor of poor prognosis (Hishikawa et al, 1997).…”