Overexpression of DNA Methyltransferases 1, 3a, and 3b Significantly Correlates With Retinoblastoma Tumorigenesis

Abstract

DNA methyltransferases (DNMTs) 1, 3a, and 3b affect DNA promoter methylation; studies have suggested that they have important roles in the development of cancers. In this study, we analyzed the expression of DNMTs 1, 3a, and 3b; the MIB-1 labeling index; and their clinical significance in 6 normal retinas and 62 retinoblastomas using immunohistochemical analysis. We found that DNMT proteins were not expressed in normal retinas, whereas they were frequently expressed in retinoblastomas (DNMT1, 100%; DNMT3a, 98%; and DNMT3b, 92%). Compared with well-differentiated retinoblastomas, the expression of DNMTs 1 and 3a significantly increased in poorly differentiated retinoblastomas (P = .002 and P = .003, respectively); in addition, the frequency of their increased expression was high. DNMT1 expression was significantly higher in invasive retinoblastoma. Furthermore, the expression of DNMTs was positively correlated with the MIB-1 labeling index in retinoblastoma. Our findings suggest that the overexpression of DNMTs 1, 3a, and 3b may be related to retinoblastoma tumorigenesis and progression and may represent a novel approach for retinoblastoma therapy.

Clinicopathologic significances of nuclear expression of nuclear factor-κB transcription factors in retinoblastoma

“…Furthermore, tumour invasion is considered to be an important risk factor for metastatic retinoblastoma. A previous study indicated that high-mobility group proteins A1 and A2 (HMGA1 and 2), DNA methyltransferase1 and 3a (DNMT1 and 3a) are associated with highly malignant phenotypes and are poor prognostic indices 4 5. In this study, c-Rel expression was shown to be significantly increased in PD retinoblastomas compared with WD tumours and RelA and c-Rel expression were significantly higher in invasive retinoblastoma.…”

“…It can be speculated that the combination of bortezomib with other cytotoxic therapies, or inhibitors of other pro-survival pathways, may enhance the antitumour activity of this drug in the treatment of some cancers. A previous study indicated the association of HMGA1 and 2, and DNMT1 and 3a with tumorigenesis and progression of retinoblastoma 4 5. Further research is required to elucidate the mechanisms of NF-κB pathways in this disease and to develop therapeutic approaches with combinations of inhibitors of NF-κB and HMGA1 and 2, DNMTs or other factors such as the RB gene reported to be involved in retinoblastoma pathogenesis.…”

DNA methylation by DNMT1 and DNMT3b methyltransferases is driven by the MUC1-C oncoprotein in human carcinoma cells

“…Moreover, DNMT3a and DNMT3b establish de novo postreplicative DNA methylation patterns (7; 8). DNMT1, DNMT3a and DNMT3b are often overexpressed in cancer cells (9–11). Transcriptional activation of the DNMT1, DNMT3a and DNMT3b genes has been linked to activation of the RAS-JUN pathway (12; 13) and to binding of the Sp1 and Sp3 zinc finger proteins to their promoters (14; 15).…”

Combined effects of DNA methyltransferase 1 and 3A polymorphisms and urinary total arsenic levels on the risk for clear cell renal cell carcinoma

“…A study showed that DNMT1 and DNMT3A mRNA levels were higher in human kidney tumor tissues than in adjacent normal tissues (Robertson et al, 1999), and the expression of DNMT1 and DNMT3A proteins was higher in RCC tumors than in nontumor tissues (Li et al, 2014b). High DNMT1 and DNMT3A expression also was found in poorly differentiated retinoblastoma (Qu et al, 2010) and advanced uterine cervical carcinoma (Luczak et al, 2012). Cao et al reported that DNMT1 and DNMT3A expression was higher in human gastric carcinoma tissues than in adjacent normal gastric epithelial tissues, and DNMT3A expression was significantly related to poor survival (Cao et al, 2014).…”