TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

Takayama, Ken Ichi; Misawa, Aya; Suzuki, Takashi; Takagi, Kiyoshi; Hayashizaki, Yoshihide; Fujimura, Tetsuya; Homma, Yukio; Takahashi, Satoru; Urano, Tomohiko; Inoue, Satoshi

doi:10.1038/ncomms9219

Cited by 93 publications

(95 citation statements)

References 56 publications

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“…We confirmed the effect of TET2 KD using a second independent siRNA (siTET2-4) recently described by Takayama et al 37 (Figure 1a; Supplementary Table S3). We performed three independent treatments of LNCaP cells with siTET2-4 or a GC-matched scrambled siRNA control (scRNA) in the absence and presence of DHT.…”

Section: Resultssupporting

confidence: 89%

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

Nickerson

Das

et al. 2016

Oncogene

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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.

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Section: Resultssupporting

confidence: 89%

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

Nickerson

Das

et al. 2016

Oncogene

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“…Therefore, we chose this lncRNA for further study. Our ChIP-seq data (26,27) revealed ARBS in the promoter region (Chr12: 93,963,629 -93,965,465 (hg19), ϩ1.5 kbp-291 bp from the transcriptional start site (TSS) of NR_038263). Interestingly, although its expression was repressed after 48 h of androgen treatment in LNCaP cells, it was further induced even after 72 h of androgen stimulation in LTAD cells (Fig.…”

Section: Identification Of Androgen-induced Lncrnas By Directionalmentioning

confidence: 99%

Androgen-induced Long Noncoding RNA (lncRNA) SOCS2-AS1 Promotes Cell Growth and Inhibits Apoptosis in Prostate Cancer Cells

Misawa

Takayama

Urano

et al. 2016

Journal of Biological Chemistry

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131

108

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Long noncoding RNAs (lncRNA) have been associated with the development of cancer. However, the interplay between lncRNAs and androgen receptor (AR) signaling in prostate cancer is still unclear. Here, we identified lncRNAs induced by androgen in AR-positive prostate cancer cells, where induction was abolished by AR knockdown as well as an anti-androgen, bicalutamide. By combining these data, we identified an androgen-regulated lncRNA, suppressor of cytokine signaling 2-antisense transcript 1 (SOCS2-AS1), the expression of which was higher in castration-resistant prostate cancer model cells, i.e. long-term androgen-deprived (LTAD) cells, than in parental androgen-dependent LNCaP cells. SOCS2-AS1 promoted castration-resistant and androgen-dependent cell growth. We found that SOCS2-AS1 knockdown up-regulated genes related to the apoptosis pathway, including tumor necrosis factor superfamily 10 (TNFSF10), and sensitized prostate cancer cells to docetaxel treatment. Moreover, we also demonstrated that SOCS2-AS1 promotes androgen signaling by modulating the epigenetic control for AR target genes including TNFSF10. These findings suggest that SOCS2-AS1 plays an important role in the development of castration-resistant prostate cancer by repressing apoptosis.

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“…Importantly, I have demonstrated that miR-29 family and miR-22 are highly induced by androgen in hormone-therapy resistant prostate cancer [25]. In prostate cancer clinical samples the expression level of miR-29a/b is negatively associated with that of its target gene, TET2.…”

Section: Prostate Aging and Cancer Progression Is Prominent In Aged Mmentioning

confidence: 99%

“…(B) Androgen-induced miRNA mediated TET2 repression inhibits 5-hmC modifications in FOXA1 occupied enhancer regions. By removal of 5-hmC, FOXA1 is activated and induce FOXA1 or AR-regulated genes [25]. (C) The role of enhancer RNA (eRNA) or other AR interacting lncRNA.…”

Section: The Androgen Receptor (Ar) Functions As a Nuclear Receptor Tmentioning

confidence: 99%

The biological and clinical advances of androgen receptor function in age-related diseases and cancer [Review]

Takayama

2017

Endocr J

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Abstract. Hormonal alterations with aging contribute to the pathogenesis of several diseases. Androgens mediate their effects predominantly through binding to the androgen receptor (AR), a member of the ligand-dependent nuclear receptor superfamily. By androgen treatment, AR is recruited to specific genomic loci dependent on tissue specific pioneer factors to regulate target gene expression. Recent studies have revealed the epigenetic modulation by AR-associated histone modifiers and the roles of non-coding RNAs in AR signaling. Androgens are male sex hormone to induce differentiation of the male reproductive system required for the establishment of adult sexual function. As shown by several reports using AR knockout mouse models, androgens also have anabolic functions in several tissues such as bone, muscle and central nervous systems. Notably, AR has a central role in prostate cancer progression. Prostate cancer is the most frequently diagnosed cancer in men. Androgen-deprivation therapy for cancer patients and decline of serum androgen with aging promote several diseases associated with aging and quality of life of older men such as osteoporosis, sarcopenia and dementia. Thus, androgen replacement therapy for treating late onset hypogonadism (LOH) or new epigenetic regulators have the potential to overcome the symptoms caused by the low androgen, although adverse effects for cardiovascular diseases have been reported. Given the increasing longevity and consequent rise of age-related diseases and prostate cancer patients, a more understanding of the AR actions in male health remains a high research priority.

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TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

Cited by 93 publications

References 56 publications

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

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

Androgen-induced Long Noncoding RNA (lncRNA) SOCS2-AS1 Promotes Cell Growth and Inhibits Apoptosis in Prostate Cancer Cells

The biological and clinical advances of androgen receptor function in age-related diseases and cancer [Review]

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