Testis specific Y-like 5: gene expression, methylation and implications for drug sensitivity in prostate carcinoma

被引:16
作者
Kumar, Senthil R. [1 ]
Bryan, Jeffrey N. [1 ]
Esebua, Magda [2 ]
Amos-Landgraf, James [3 ]
May, Tanner J. [1 ]
机构
[1] Univ Missouri, Coll Vet Med & Surg, Comparat Oncol Radiobiol & Epigenet Lab, 1600 E Rollins,W-143 Vet Med Bldg, Columbia, MO 65211 USA
[2] Univ Missouri, Sch Med, Dept Pathol & Anat Sci, Columbia, MO 65212 USA
[3] Univ Missouri, Dept Vet Pathobiol, Columbia, MO 65211 USA
关键词
Prostate carcinoma; Putative tumor suppressor gene; Drug sensitivity; Methylation; CANCER-CELLS; DNA METHYLATION; RESISTANCE; PROTEIN; TSPYL5; CHEMOSENSITIVITY; LOCALIZATION; STABILITY; CISPLATIN; FAMILY;
D O I
10.1186/s12885-017-3134-7
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: TSPYL5, a putative tumor suppressor gene, belongs to the nucleosome assembly protein family. The chromosomal location of the TSPYL5 gene is 8Q22.1, and its exact role in prostate cancer etiology remains unclear. Further TSPYL5 gene and protein expression in prostate carcinoma cells and diseased tissues including its susceptibility for epigenetic silencing is unknown. Also, not known is the variation in TSPYL5 protein expression with regards to progression of prostatic carcinoma and its possible role in drug sensitivity. Methods: TSPYL5, DNMT-1 and DNMT-B gene expression in DU145, LNCaP and RWPE-1 cells and prostate tumor tissues was analyzed by qRT-PCR and RT-PCR. Demethylation experiments were done by treating DU145 and LNCaP cells with 5-aza-2'-deoxycytidine in vitro. Methylation analysis of TSPYL5 gene was performed by methylation specific PCR and pyrosequencing. TSPYL5 protein expression in benign and diseased prostate tumor tissues was performed by immunohistochemistry and in the cells by Western blotting. Results: TSPYL5 was differentially expressed in non-tumorigenic prostate epithelial cells (RWPE-1), androgen independent (DU145), dependent (LNCaP) prostate carcinoma cells and tissues. Methylation-specific PCR and pyrosequencing analysis identified an inverse relationship between DNA methylation and expression leading to the silencing of TSPYL5 gene. Treatment of prostate carcinoma cells in which TSPYL5 was absent or low (DU145 and LNCaP) with the demethylating agent 5-aza-2'-deoxycytidine upregulated its expression in these cells. Immunohistochemical studies clearly identified TSPYL5 protein in benign tissue and in tumors with Gleason score (GS) of 6 and 7. TSPYL5 protein levels were very low in tumors of GS >= 8. TSPYL5 overexpression in LNCaP cells increased the cell sensitivity to chemotherapy drugs such as docetaxel and paclitaxel, as measured by the cellular viability. Furthermore, the cells also exhibited reduced CDKN1A expression with only marginal reduction in pAKT. Conclusions: Decrease in TSPYL5 protein in advanced tumors might possibly function as an indicator of prostate tumor progression. Its absence due to methylation-induced silencing can lead to reduced drug sensitivity in prostate carcinoma.
引用
收藏
页数:13
相关论文
共 41 条
[1]   CPG-RICH ISLANDS AND THE FUNCTION OF DNA METHYLATION [J].
BIRD, AP .
NATURE, 1986, 321 (6067) :209-213
[2]   The intricacies of p21 phosphorylation - Protein/protein interactions, subcellular localization and stability [J].
Child, Emma S. ;
Mann, David J. .
CELL CYCLE, 2006, 5 (12) :1313-1319
[3]   Sensitive and quantitative universal Pyrosequencing™ methylation analysis of CpG sites [J].
Colella, S ;
Shen, L ;
Baggerly, KA ;
Issa, JPJ ;
Krahe, R .
BIOTECHNIQUES, 2003, 35 (01) :146-+
[4]   Sensitive detection of DNA methylation [J].
Cottrell, SE ;
Laird, PW .
EPIGENETICS IN CANCER PREVENTION: EARLY DETECTION AND RISK ASSESSMENT, 2003, 983 :120-130
[5]   Overtreatment of Men With Low-Risk Prostate Cancer and Significant Comorbidity [J].
Daskivich, Timothy J. ;
Chamie, Karim ;
Kwan, Lorna ;
Labo, Jessica ;
Palvolgyi, Roland ;
Dash, Atreya ;
Greenfield, Sheldon ;
Litwin, Mark S. .
CANCER, 2011, 117 (10) :2058-2066
[6]   De novo quantitative bisulfite sequencing using the pyrosequencing technology [J].
Dupont, JM ;
Tost, J ;
Jammes, H ;
Gut, NG .
ANALYTICAL BIOCHEMISTRY, 2004, 333 (01) :119-127
[7]   DNA methylation in cancer: too much, but also too little [J].
Ehrlich, M .
ONCOGENE, 2002, 21 (35) :5400-5413
[8]   TSPYL5 suppresses p53 levels and function by physical interaction with USP7 [J].
Epping, Mirjam T. ;
Meijer, Lars A. T. ;
Krijgsman, Oscar ;
Bos, Johannes L. ;
Pandolfi, Pier Paolo ;
Bernards, Rene .
NATURE CELL BIOLOGY, 2011, 13 (01) :102-U249
[9]   The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma [J].
Epstein, JI ;
Allsbrook, WC ;
Amin, MB ;
Egevad, LL ;
Bastacky, S ;
Beltrán, AL ;
Berner, A ;
Billis, A ;
Boccon-Gibod, L ;
Cheng, L ;
Civantos, F ;
Cohen, C ;
Cohen, MB ;
Datta, M ;
Davis, C ;
Delahunt, B ;
Delprado, W ;
Eble, JN ;
Foster, CS ;
Furusato, M ;
Gaudin, PB ;
Grignon, DJ ;
Humphrey, PA ;
Iczkowski, KA ;
Jones, EC ;
Lucia, S ;
McCue, PA ;
Nazeer, T ;
Oliva, E ;
Pan, CC ;
Pizov, G ;
Reuter, V ;
Samaratunga, H ;
Sebo, T ;
Sesterhenn, I ;
Shevchuk, M ;
Srigley, JR ;
Suzigan, S ;
Takahashi, H ;
Tamboli, P ;
Tan, PH ;
Têtu, B ;
Tickoo, S ;
Tomaszewski, JE ;
Troncoso, P ;
Tsuzuki, T ;
True, LD ;
van der Kwast, T ;
Wheeler, TM ;
Wojno, KJ .
AMERICAN JOURNAL OF SURGICAL PATHOLOGY, 2005, 29 (09) :1228-1242
[10]   Resistance to Docetaxel-Induced Apoptosis in Prostate Cancer Cells by p38/p53/p21 Signaling [J].
Gan, Lu ;
Wang, Jianlin ;
Xu, Huibi ;
Yang, Xiangliang .
PROSTATE, 2011, 71 (11) :1158-1166