Daisuke Obinata1, Shogo Takada2, Ken-ichi Takayama3, Tomohiko Urano3, Akiko Ito2, Daisaku Ashikari1, Kyoko Fujiwara4, Yuta Yamada5, Taro Murata5, Jinpei Kumagai5, Tetsuya Fujimura5, Kazuhiro Ikeda6, Kuniko Horie-Inoue6, Yukio Homma5, Satoru Takahashi2, Satoshi Inoue7. 1. Department of Urology, Nihon University School of Medicine, Japan; Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Japan. 2. Department of Urology, Nihon University School of Medicine, Japan. 3. Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Japan; Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Japan; Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Japan. 4. Division of General Medicine, Department of Medicine, Nihon University School of Medicine, Japan. 5. Department of Urology, Graduate School of Medicine, The University of Tokyo, Japan. 6. Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Japan. 7. Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Japan; Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Japan; Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Japan. Electronic address: INOUE-GER@h.u-tokyo.ac.jp.
Abstract
BACKGROUND: The androgen receptor (AR) plays a key role in the development of prostate cancer. AR signalling mediates the expression of androgen-responsive genes, which are involved in prostate cancer development and progression. Our previous chromatin immunoprecipitation study showed that the region of abhydrolase domain containing 2 (ABHD2) includes a functional androgen receptor binding site. In this study, we demonstrated that ABHD2 is a novel androgen-responsive gene that is overexpressed in human prostate cancer tissues. METHODS: The expression levels of ABHD2 in androgen-sensitive cells were evaluated by quantitative reverse transcription polymerase chain reaction and western-blot analyses. LNCaP and VCaP cells with ABHD2 overexpression or short interfering RNA (siRNA) knockdown were used for functional analyses. ABHD2 expression was examined in clinical samples of prostate cancer by immunohistochemistry. RESULTS: We showed that ABHD2 expression is increased by androgen in LNCaP and VCaP cells. This androgen-induced ABHD2 expression was diminished by bicalutamide. While stable expression of ABHD2 affected the enhancement of LNCaP cell proliferation and migration, siRNA-mediated ABHD2 knockdown suppressed cell proliferation and migration. In addition, the siRNA treatment significantly repressed the tumour growth derived from LNCaP cells in athymic mice. Immunohistochemical analysis of ABHD2 expression in tumour specimens showed a positive correlation of ABHD2 immunoreactivity with high Gleason score and pathological N stage. Moreover, patients with high immunoreactivity of ABHD2 showed low cancer-specific survival rates and a resistance to docetaxel-based chemotherapy. CONCLUSION: ABHD2 is a novel androgen-regulated gene that can promote prostate cancer growth and resistance to chemotherapy, and is a novel target for diagnosis and treatment of prostate cancer.
BACKGROUND: The androgen receptor (AR) plays a key role in the development of prostate cancer. AR signalling mediates the expression of androgen-responsive genes, which are involved in prostate cancer development and progression. Our previous chromatin immunoprecipitation study showed that the region of abhydrolase domain containing 2 (ABHD2) includes a functional androgen receptor binding site. In this study, we demonstrated that ABHD2 is a novel androgen-responsive gene that is overexpressed in humanprostate cancer tissues. METHODS: The expression levels of ABHD2 in androgen-sensitive cells were evaluated by quantitative reverse transcription polymerase chain reaction and western-blot analyses. LNCaP and VCaP cells with ABHD2 overexpression or short interfering RNA (siRNA) knockdown were used for functional analyses. ABHD2 expression was examined in clinical samples of prostate cancer by immunohistochemistry. RESULTS: We showed that ABHD2 expression is increased by androgen in LNCaP and VCaP cells. This androgen-induced ABHD2 expression was diminished by bicalutamide. While stable expression of ABHD2 affected the enhancement of LNCaP cell proliferation and migration, siRNA-mediated ABHD2 knockdown suppressed cell proliferation and migration. In addition, the siRNA treatment significantly repressed the tumour growth derived from LNCaP cells in athymic mice. Immunohistochemical analysis of ABHD2 expression in tumour specimens showed a positive correlation of ABHD2 immunoreactivity with high Gleason score and pathological N stage. Moreover, patients with high immunoreactivity of ABHD2 showed low cancer-specific survival rates and a resistance to docetaxel-based chemotherapy. CONCLUSION:ABHD2 is a novel androgen-regulated gene that can promote prostate cancer growth and resistance to chemotherapy, and is a novel target for diagnosis and treatment of prostate cancer.
Authors: Anders E Berglund; Robert J Rounbehler; Travis Gerke; Shivanshu Awasthi; Chia-Ho Cheng; Mandeep Takhar; Elai Davicioni; Mohammed Alshalalfa; Nicholas Erho; Eric A Klein; Stephen J Freedland; Ashley E Ross; Edward M Schaeffer; Bruce J Trock; Robert B Den; John L Cleveland; Jong Y Park; Jasreman Dhillon; Kosj Yamoah Journal: Prostate Cancer Prostatic Dis Date: 2018-10-26 Impact factor: 5.554