Tracing TET1 expression in prostate cancer: discovery of malignant cells with a distinct oncogenic signature

Abstract

Background Ten–eleven translocation methylcytosine dioxygenase 1 (TET1) is involved in DNA demethylation and transcriptional regulation, plays a key role in the maintenance of stem cell pluripotency, and is dysregulated in malignant cells. The identification of cancer stem cells (CSCs) driving tumor growth and metastasis is the primary objective of biomarker discovery in aggressive prostate cancer (PCa). In this context, we analyzed TET1 expression in PCa. Methods A large-scale immunohistochemical analysis of TET1 was performed in normal prostate (NOR) and PCa using conventional slides (50 PCa specimens) and tissue microarrays (669 NOR and 1371 PCa tissue cores from 371 PCa specimens). Western blotting, RT-qPCR, and 450 K methylation array analyses were performed on PCa cell lines. Genome-wide correlation, gene regulatory network, and functional genomics studies were performed using publicly available data sources and bioinformatics tools. Results In NOR, TET1 was exclusively expressed in normal cytokeratin 903 (CK903)–positive basal cells. In PCa, TET1 was frequently detected in alpha-methylacyl-CoA racemase (AMACR)–positive tumor cell clusters and was detectable at all tumor stages and Gleason scores. Pearson’s correlation analyses of PCa revealed 626 TET1-coactivated genes (r > 0.5) primarily encoding chromatin remodeling and mitotic factors. Moreover, signaling pathways regulating antiviral processes (62 zinc finger, ZNF, antiviral proteins) and the pluripotency of stem cells were activated. A significant proportion of detected genes exhibited TET1-correlated promoter hypomethylation. There were 161 genes encoding transcription factors (TFs), of which 133 were ZNF-TFs with promoter binding sites in TET1 and in the vast majority of TET1-coactivated genes. Conclusions TET1-expressing cells are an integral part of PCa and may represent CSCs with oncogenic potential.

The expression and clinical value of LRP11, FUBP1 and TET1 in cervical cancer

“…Diseases associated with TET1 include Glioblastoma and Rett Syndrome and cervical cancer. The important paralog of this gene is TET2 (13)(14)(15)(16)(17). Figure 1(C) shows the location of this gene on the chromosome.…”

Aberrations of DNA methylation in cancer

“…Было выявлено, что в тканях карциномы простаты повышенная экспрессия ТЕТ1 коррелирует с деметилированием промотора и усиленной экспрессией генов, кодирующих факторы транскрипции, что опосредует активацию сигнальных путей, регулирующих противовирусный ответ и плюрипотентность стволовых клеток [112]. Тем не менее пониженный уровень экспрессии ТЕТ1 в ряде нозологий связан с опухолевым ростом, повышенной клеточной инвазией и метастазированием.…”

Active DNA Demethylase, TET1, Increases Oxidative Phosphorylation and Sensitizes Ovarian Cancer Stem Cells to Mitochondrial Complex I Inhibitor

“…Although the role of TET1 in cancer biology remains poorly understood thus far, the enzymatic role of TET proteins in the mammalian DNA demethylation pathway suggests the involvement of epigenetic dysregulation in various human cancers [ 7 , 8 ]. Recent investigations have suggested an oncogenic role of TET1 in solid cancers [ 9 , 10 , 11 ] and its involvement in the maintenance of cancer stem cells (CSCs) in prostate cancer [ 12 ], triple-negative breast cancer (TNBC) [ 13 , 14 ], and endometrial cancer [ 15 ]. In TNBC CSCs, TET1 is essential for their maintenance.…”