TET2 binds the androgen receptor and loss is associated with prostate cancer

Abstract

Genetic alterations associated with prostate cancer (PCa) may be identified by sequencing metastatic tumor genomes to identify molecular markers at this lethal stage of disease. Previously, we characterized somatic alterations in metastatic tumors in the methylcytosine dioxygenase ten-eleven translocation 2 (TET2), which is altered in 5–15% of myeloid, kidney, colon and prostate cancers. Genome-wide association studies previously identified non-coding risk variants associated with PCa and melanoma. We performed fine-mapping of PCa risk across TET2 using genotypes from the PEGASUS case-control cohort and identified six new risk variants in introns 1 and 2. Oligonucleotides containing two risk variants were bound by the transcription factor octamer-binding protein 1 (Oct1/POU2F1) and TET2 and Oct1 expression were positively correlated in prostate tumors. TET2 is expressed in normal prostate tissue and reduced in a subset of tumors from the Cancer Genome Atlas (TCGA). Small interfering RNA (siRNA)-mediated TET2 knockdown (KD) increases LNCaP cell proliferation, migration, and wound healing, verifying loss drives a cancer phenotype. Endogenous TET2 bound the androgen receptor (AR) and AR-coactivator proteins in LNCaP cell extracts, and TET2 KD increases prostate-specific antigen (KLK3/PSA) expression. Published data reveal TET2 binding sites and hydroxymethylcytosine (hmC) proximal to KLK3. A gene co-expression network identified using TCGA prostate tumor RNA-sequencing identifies co-regulated cancer genes associated with 2-oxoglutarate (2-OG) and succinate metabolism, including TET2, lysine demethylase (KDM) KDM6A, BRCA1-associated BAP1, and citric acid cycle enzymes IDH1/2, SDHA/B, and FH. The co-expression signature is conserved across 31 TCGA cancers suggesting a putative role for TET2 as an energy sensor (of 2-OG) that modifies aspects of androgen-AR signaling. Decreased TET2 mRNA expression in TCGA PCa tumors is strongly associated with reduced patient survival indicating reduced expression in tumors maybe an informative biomarker of disease progression and perhaps metastatic disease.

TET2 in Normal and Malignant Hematopoiesis

“…In addition to melanoma, TET2 has been shown to be down-regulated in an androgendependent manner in prostate cancer, with lower expression conferring worse prognosis for patients (Nickerson et al 2016). In colorectal cancer, TET2 has been shown to be excluded from the nucleus , with similar findings for TET1 in glioma (Waha et al 2012).…”

Genetics and biology of prostate cancer

“…Interestingly, TGF-β was shown to regulate the expression of DNMTs in prostate cancer, with their expression correlating with aggressiveness and recurrence (Zhang et al 2011b). Both TET1 and TET2 were shown to play a tumor-suppressive role in prostate cancer through regulation of cell proliferation, migration, and invasion (Hsu et al 2012;Nickerson et al 2017).…”

Values of 5mC, 5hmC, and TET2 for identifying the presence and progression of breast precancerous lesion

“…Five‐methylcytosine (5mC) is a regulator of DNA methylation, which is a process crucial to tumorigenesis; in addition, 5mC can be switched into 5‐hydroxymethylcytosine (5hmC) by the activations of ten‐eleven translocation (TET) family, including TET2 . Previous studies have revealed the roles of 5mC, 5hmC, and TET2 in multiple cancers, including regulating cancer progression and serving as diagnostic or prognostic biomarkers in clinical practice . More importantly, there are reports illuminating that 5mC, 5hmC, and TET2 also participate in breast cancer etiology, including the regulation of tumor suppressor genes and DNA methylation .…”