Tumor suppressor REIC/DKK-3 and co-chaperone SGTA: Their interaction and roles in the androgen sensitivity.

Masami Morimatsu,Hideo Ueki,Oumaporn Rungsuriyawiboon,Yuiko Kato,Hiromi Kumon,Chihiro Udagawa,Yasutomo Nasu,Toshinori Omi,Toshina Ishiguro-Oonuma,Masami Watanabe,Masaki Michishita,Yuichi Ariyoshi,Daigo Azakami,Kazuhiko Ochiai

doi:10.18632/oncotarget.6488

Abstract

REIC/DKK-3 is a tumor suppressor, however, its intracellular physiological functions and interacting molecules have not been fully clarified. Using yeast two-hybrid screening, we found that small glutamine-rich tetratricopeptide repeat-containing protein α (SGTA), known as a negative modulator of cytoplasmic androgen receptor (AR) signaling, is a novel interacting partner of REIC/DKK-3. Mammalian two-hybrid and pull-down assay results indicated that the SGTA-REIC/DKK-3 interaction involved the N-terminal regions of both REIC/DKK-3 and SGTA and that REIC/DKK-3 interfered with the dimerization of SGTA, which is a component of the AR complex and a suppressor of dynein motor-dependent AR transport and signaling. A reporter assay in human prostate cancer cells that displayed suppressed AR signaling by SGTA showed recovery of AR signaling by REIC/DKK-3 expression. Considering these results and our previous data that REIC/DKK-3 interacts with the dynein light chain TCTEX-1, we propose that the REIC/DKK-3 protein interferes with SGTA dimerization, promotes dynein-dependent AR transport and then upregulates AR signaling.

Highlights

Reduced expression in immortalized cells (REIC), which was discovered initially as a tumor suppressor gene, is identical to the Dickkopf-3 (DKK-3) gene, which is a member of the Dickkopf gene family [1]
We demonstrated that small glutamine-rich tetratricopeptide repeatcontaining protein α (SGTA), which is known to bind to androgen receptor (AR) and heat shock protein 70 (HSP70)/HSP90 proteins [22,23,24], is a novel REIC/DKK-3-binding protein
The results indicate that the interaction between REIC/DKK-3 and SGTA involves the N-terminal regions of both proteins

Summary

Introduction

Reduced expression in immortalized cells (REIC), which was discovered initially as a tumor suppressor gene, is identical to the Dickkopf-3 (DKK-3) gene, which is a member of the Dickkopf gene family [1]. REIC/DKK3 is expressed ubiquitously in normal cells, whereas its expression is downregulated significantly in various types of cancer cells, including prostate cancer [2,3,4]. We and other investigators have demonstrated that REIC/DKK-3 overexpression by adenoviral or plasmid vectors induces apoptosis in multiple cancer cell lines, but not in normal cells, via c-Jun-NH2-terminal kinase (JNK) and c-Jun activation [5,6,7,8,9,10]. Our previous study indicated that REIC/DKK-3 overexpression by adenoviral vectors triggers apoptosis induction via endoplasmic reticulum (ER) stress signaling [11,12]. Various studies have shown that REIC/DKK-3 downregulation is closely associated with the pathological malignancy of clinical specimens of various cancer types [2,13,14].

Methods

Results

Conclusion