Loss of DOK2 induces carboplatin resistance in ovarian cancer via suppression of apoptosis

被引:42
作者
Lum, Elena [1 ]
Vigliotti, Michele [1 ]
Banerjee, Nilanjana [2 ]
Cutter, Noelle [1 ]
Wrzeszczynski, Kazimierz O. [1 ]
Khan, Sohail [3 ]
Kamalakaran, Sitharthan [2 ]
Levine, Douglas A. [4 ]
Dimitrova, Nevenka [2 ]
Lucito, Robert [5 ]
机构
[1] Cold Spring Harbor, Woodbury, NY USA
[2] Philips Inc, Briarcliff Manor, NY USA
[3] SUNY Stony Brook, Stony Brook, NY 11794 USA
[4] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA
[5] Hofstra North Shore LIJ Sch Med, Hempstead, NY USA
关键词
Epigenetics; Platinum resistance; Genomics; Ovarian Cancer; Apoptosis; OLIGONUCLEOTIDE MICROARRAY ANALYSIS; ANCHORAGE-INDEPENDENT GROWTH; HIGH-RESOLUTION METHOD; FACTOR-I-ALPHA; CROSS-TALK; PROGNOSTIC-SIGNIFICANCE; EXPRESSION; CELLS; MECHANISMS; ANOIKIS;
D O I
10.1016/j.ygyno.2013.05.002
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Objective. Ovarian cancers are highly heterogeneous and while chemotherapy is the preferred treatment many patients are intrinsically resistant or quickly develop resistance. Furthermore, all tumors that recur ultimately become resistant. Recent evidence suggests that epigenetic deregulation may be a key factor in the onset and maintenance of chemoresistance. We set out to identify epigenetically silenced genes that affect chemoresistance. Methods. The epigenomes of a total of 45 ovarian samples were analyzed to identify epigenetically altered genes that segregate with platinum response, and further filtered with expression data to identify genes that were suppressed. A tissue culture carboplatin resistance screen was utilized to functionally validate this set of candidate platinum resistance genes. Results. Our screen correctly identified 19 genes that when suppressed altered the chemoresistance of the cells in culture. Of the genes identified in the screen we further characterized one gene, docking protein 2 (DOK2), an adapter protein downstream of tyrosine kinase, to determine if we could elucidate the mechanism by which it increased resistance. The loss of DOK2 decreased the level of apoptosis in response to carboplatin. Furthermore, in cells with reduced DOK2, the level of anoikis was decreased. Conclusions. We have developed a screening methodology that analyzes the epigenome and informatically identifies candidate genes followed by in vitro culture screening of the candidate genes. To validate our screening methodology we further characterized one candidate gene, DOK2, and showed that loss of DOK2 induces chemotherapy resistance by decreasing the level of apoptosis in response to treatment. (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved.
引用
收藏
页码:369 / 376
页数:8
相关论文
共 44 条
[1]   Mutational and expressional analysis of a haploinsufficient tumor suppressor gene DOK2 in gastric and colorectal cancers [J].
An, Chang Hyeok ;
Kim, Min Sung ;
Yoo, Nam Jin ;
Lee, Sug Hyung .
APMIS, 2011, 119 (08) :562-564
[2]  
Bachtiary B, 2003, CLIN CANCER RES, V9, P2234
[3]   Role of epigenomics in ovarian and endometrial cancers [J].
Balch, Curtis ;
Matei, Daniela E. ;
Huang, Tim H-M ;
Nephew, Kenneth P. .
EPIGENOMICS, 2010, 2 (03) :419-447
[4]   The biology of ovarian cancer: new opportunities for translation [J].
Bast, Robert C., Jr. ;
Hennessy, Bryan ;
Mills, Gordon B. .
NATURE REVIEWS CANCER, 2009, 9 (06) :415-428
[5]   Integrated genomic analyses of ovarian carcinoma [J].
Bell, D. ;
Berchuck, A. ;
Birrer, M. ;
Chien, J. ;
Cramer, D. W. ;
Dao, F. ;
Dhir, R. ;
DiSaia, P. ;
Gabra, H. ;
Glenn, P. ;
Godwin, A. K. ;
Gross, J. ;
Hartmann, L. ;
Huang, M. ;
Huntsman, D. G. ;
Iacocca, M. ;
Imielinski, M. ;
Kalloger, S. ;
Karlan, B. Y. ;
Levine, D. A. ;
Mills, G. B. ;
Morrison, C. ;
Mutch, D. ;
Olvera, N. ;
Orsulic, S. ;
Park, K. ;
Petrelli, N. ;
Rabeno, B. ;
Rader, J. S. ;
Sikic, B. I. ;
Smith-McCune, K. ;
Sood, A. K. ;
Bowtell, D. ;
Penny, R. ;
Testa, J. R. ;
Chang, K. ;
Dinh, H. H. ;
Drummond, J. A. ;
Fowler, G. ;
Gunaratne, P. ;
Hawes, A. C. ;
Kovar, C. L. ;
Lewis, L. R. ;
Morgan, M. B. ;
Newsham, I. F. ;
Santibanez, J. ;
Reid, J. G. ;
Trevino, L. R. ;
Wu, Y. -Q. ;
Wang, M. .
NATURE, 2011, 474 (7353) :609-615
[6]   CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING [J].
BENJAMINI, Y ;
HOCHBERG, Y .
JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) :289-300
[7]   Identification of DOK genes as lung tumor suppressors [J].
Berger, Alice H. ;
Niki, Masaru ;
Morotti, Alessandro ;
Taylor, Barry S. ;
Socci, Nicholas D. ;
Viale, Agnes ;
Brennan, Cameron ;
Szoke, Janos ;
Motoi, Noriko ;
Rothman, Paul B. ;
Teruya-Feldstein, Julie ;
Gerald, William L. ;
Ladanyi, Marc ;
Pandolfi, Pier Paolo .
NATURE GENETICS, 2010, 42 (03) :216-U27
[8]   A comparison of normalization methods for high density oligonucleotide array data based on variance and bias [J].
Bolstad, BM ;
Irizarry, RA ;
Åstrand, M ;
Speed, TP .
BIOINFORMATICS, 2003, 19 (02) :185-193
[9]   Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells [J].
Chan, David W. ;
Liu, Vincent W. S. ;
Tsao, George S. W. ;
Yao, Kwok-Ming ;
Furukawa, Toru ;
Chan, Karen K. L. ;
Ngan, Hextan Y. S. .
CARCINOGENESIS, 2008, 29 (09) :1742-1750
[10]   CORRELATION OF PATTERNS OF ANCHORAGE-INDEPENDENT GROWTH WITH INVIVO BEHAVIOR OF CELLS FROM A MURINE FIBRO-SARCOMA [J].
CIFONE, MA ;
FIDLER, IJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1980, 77 (02) :1039-1043