Expression of RFG/ELE1α/ARA70 in normal and malignant prostatic epithelial cell cultures and lines: Regulation by methylation and sex steroids

Seshadri Tekur, Kin Mang Lau, John Long, Kerry Burnstein, Shuk Mei Ho

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

RET fused gene (RFG)/ELE1α/androgen receptor-associated protein 70(ARA70) was first found to be involved in the activation of the RET proto-oncogene in thyroid neoplasm and has recently been shown to be a ligand-dependent transcriptional coregulator for androgen receptor (AR). The functionality of RFG/ELE1α/ARA70 remains controversial, and little is known about factors regulating its expression in the prostate. Of significant interest is whether this molecule is involved in prostate carcinogenesis. Using reverse transcriptase-polymerase chain reaction semiquantitation, we compared RFG/ELE1α/ARA70 mRNA levels in four prostate cancer cell lines (LNCaP, TSU-Prl, DU-145, and PC-3) with those found in primary cultures of normal prostatic epithelial cells (PrECs). In addition, we examined the effects of androgen and antiandrogen, estrogen and antiestrogen, and a demethylating agent on RFG/ELE1α/ARA70 mRNA expression levels in AR- and AR+ PC-3 cells. Reduced levels of RFG/ELE1α/ARA70 message were observed in all four prostate cancer cell lines when compared with normal PrECs in primary cultures. RFG/ELE1α/ARA70 mRNA levels in PC-3 cells, which express both estrogen receptor subtypes, were upregulated by 17β-estradiol and inhibited by the antiestrogen ICI-182780. In PC-3(AR+) cells, which were genetically engineered to express AR, exposure to androgen upregulated RFG/ELE1α/ARA70 mRNA expression, whereas treatment with 4-hydroxyflutamide lowered expression of this transcript. Furthermore, treatment of DU-145 cells, which did not express RFG/ELE1α/ARA70 transcripts, with a demethylating agent reactivated transcription of this gene. Polymerase chain reaction analyses of monochromosomal human-rodent hybrid panels localized a putative RFG/ELE1α/ARA70 isoform on human chromosome 5q31.1-31.2. In summary, we identified sex hormones and DNA hypermethylation as regulators of RFG/ELE1α/ARA70 expression in prostate cancer cells. In addition, we found reduced levels of RFG/ELE1α/ARA70 expression in prostate cancer cell lines when compared with expression levels in normal PrECs in culture. These findings suggest that RFG/ELE1α/ARA70 may be involved prostate carcinogenesis and that it may serve as a key mediator of estrogen-androgen synergism.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalMolecular Carcinogenesis
Volume30
Issue number1
DOIs
StatePublished - Feb 19 2001

Keywords

  • 4-Hydroxy-flutamide
  • Androgen action
  • Androgen receptor coactivator
  • BPH-1
  • DNA methylation
  • DU-145
  • Estradiol-17β
  • Estrogen action
  • ICI-182780
  • LNCaP
  • PC-3
  • Prostate neoplasm
  • Steroid hormone coregulator
  • TSU-Pr1

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

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