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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

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.

Details

Original languageEnglish
Article number211
Pages (from-to)211
JournalClinical epigenetics
Volume13
Issue number1
Publication statusPublished - 29 Nov 2021
Peer-reviewedYes

External IDs

PubMedCentral PMC8630881
Scopus 85120179304
ORCID /0000-0002-8691-8423/work/142236014

Keywords

Sustainable Development Goals

Keywords

  • Aged, DNA Methylation/genetics, Gene Expression/genetics, Humans, Male, Middle Aged, Mixed Function Oxygenases/analysis, Prostatic Neoplasms/genetics, Proto-Oncogene Proteins/analysis