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TRAF2 Is an NF-ΚB-Activating Oncogene in Epithelial

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TRAF2 Is an NF-ΚB-Activating Oncogene in Epithelial Oncogene (2015) 34, 209–216 & 2015 Macmillan Publishers Limited All rights reserved 0950-9232/15 www.nature.com/onc ORIGINAL ARTICLE TRAF2 is an NF-kB-activating oncogene in epithelial cancers RR Shen1,2,3, AY Zhou1,2,3, E Kim1,2,3, JT O’Connell1,2,3, D Hagerstrand1,2,3, R Beroukhim1,2,3 and WC Hahn1,2,3 Aberrant nuclear factor (NF)-kB activation is frequently observed in human cancers. Genome characterization efforts have identified genetic alterations in multiple components of the NF-kB pathway, some of which have been shown to be essential for cancer initiation and tumor maintenance. Here, using patient tumors and cancer cell lines, we identify the NF-kB regulator, TRAF2 (tumor necrosis factor (TNF) receptor-associated factor 2), as an oncogene that is recurrently amplified and rearranged in 15% of human epithelial cancers. Suppression of TRAF2 in cancer cells harboring TRAF2 copy number gain inhibits proliferation, NF-kB activation, anchorage-independent growth and tumorigenesis. Cancer cells that are dependent on TRAF2 also require NF-kB for survival. The phosphorylation of TRAF2 at serine 11 is essential for the survival of cancer cells harboring TRAF2 amplification. Together, these observations identify TRAF2 as a frequently amplified oncogene. Oncogene (2015) 34, 209–216; doi:10.1038/onc.2013.543; published online 23 December 2013 Keywords: TRAF2; NF-kB; cancer; 9q34 amplification INTRODUCTION for the recruitment of the canonical IKK complex, the central The nuclear factor-kB (NF-kB) transcription factors play pivotal mediator of NF-kB activation. roles in immunity, inflammation, cell differentiation, proliferation Several studies suggest that TRAF2 plays an important role in and survival. In addition to its roles in immunity, constitutive cancer. In Ras-transformed cells, TRAF2 promotes resistance 28 NF-kB activity is frequently detected in both hematopoietic to stress-induced apoptosis. Similarly, TRAF2 also facilitates and epithelial cancers.1 In tumor cells, activation of NF-kB resistance to mitogen-activated protein kinase pathway inhibitors 29 occurs in response to inflammatory stimuli within a tumor micro- in BRAF V600E mutant melanoma. We recently identified TRAF2 30 environment, and cancers associated with chronic inflammation as a substrate of the IKKE breast oncogene. IKKE phospho- are dependent on NF-kB.2–7 rylates TRAF2 at serine 11 (Ser11) to activate NF-kB and promote Cancer genome characterization efforts have identified altera- malignant transformation. Here we report that TRAF2 is amplified tions in many components of the NF-kB pathway. Translocations in a substantial fraction of human epithelial cancers where it and mutations of NF-kB regulators have been identified in several functions independently of IKKE to induce tumorigenicity. different cancer types. In particular, CARD11 is both mutated and amplified in diffuse large B-cell lymphomas, and CYLD and A20 are tumor-suppressor genes deleted in familial cylindromatosis and RESULTS marginal zone B-cell lymphomas, respectively.8–12 Other NF-kB TRAF2 is amplified in a substantial fraction of human epithelial components such as CD40, NIK, NFKB1 and NFKB2 are amplified in cancers multiple myeloma.8,13–15 In solid tumors, amplification, somatic In prior work, we identified TRAF2 and the tumor suppressor CYLD mutations and chromosomal translocations of IKBKA, IKBKE as key effectors in IKKE-driven tumorigenesis in breast cancer.30,31 and IKBKB are observed in breast and prostate cancers, We found that expression of TRAF2 could replace IKKE to confer respectively.16–18 Moreover, NF-kB activity is essential in KRas- anchorage-independent growth in NIH3T3 cells and immortalized driven lung and pancreatic cancer progression that occur in a p53- human embryonic kidney cells (HA1EM) in a manner that is deficient background.19–22 Similarly, TRAF6 (tumor necrosis factor dependent on TRAF2 Ser11 phosphorylation, an activity that (TNF) receptor-associated factor 6) is an amplified oncogene promotes NF-kB activation (Supplementary Figure 1A). To present in non-small-cell lung cancers with activated RAS,23 and determine whether genetic alterations involving TRAF2 occur in loss of the tumor suppressor DAB2IP contributes to prostate human cancers, we analyzed genome-wide somatic copy number cancer progression in part through activating NF-kB signaling.24 alterations in 3131 cancer samples including 2520 carcinomas and These observations implicate aberrant NF-kB signaling in the 611 cancer cell lines.32 We identified a focal region of recurrent initiation or progression of many types of human cancers. amplification (9q34) that encompasses the TRAF2 locus. We found TRAF2 is an adaptor molecule that assembles active NF-kB increased copy number of TRAF2 in 15.1% of epithelial cancers signaling scaffolds. After TNF receptor engagement, TRAF2 forms and 13.1% of all human cancers across multiple tissue types multimeric complexes with several intracellular proteins including including breast, lung, colorectal, gastric, melanoma, ovarian and CIAP1, RIPK, TANK and TAK1, initiating a kinase cascade that esophageal cancers (Figure 1a). In contrast to broad regions of activates NF-kB and c-Jun N-terminal kinase.25,26 One key function amplification that include more than half of the chromosome arm, of TRAF2 is to facilitate Lys63 ubiquitination of components in 9q34 is significantly amplified (q ¼ 0.11) across all lineages and these scaffolds.27 TRAF2-mediated Lys63 ubiquitination is essential TRAF2 lies within a peak region containing genes most likely to be 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; 2Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA and 3Broad Institute of Harvard and MIT, Cambridge, MA, USA. Correspondence: Dr WC Hahn, Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana 1538, Boston, MA 02215, USA. E-mail: [email protected] Received 21 June 2013; revised 31 October 2013; accepted 15 November 2013; published online 23 December 2013 TRAF2 as NF-kB-activating oncogene in epithelial cancers RR Shen et al 210 a Chr 9 Mb 120 Bladder Breast Cervical Colorectal Esophageal 125 Gastric Head and Neck Hepatocellular Lung NSC 130 Lung SC Melanoma Ovarian Pancreatic Prostate 135 TRAF2 Renal Thyroid TRAF2 140 1.00 0.630.40 0.25 0.16 0.10 0.06 Significance (as q-values) b CCLE Breast (n=58) CCLE Colon (n=57) CCLE Ovarian (n=46) 8 8 8 7 7 7 6 6 6 Expression Expression Expression 5 5 5 (Arbitrary units) (Arbitrary units) (Arbitrary units) 4 4 4 (-) TRAF2 (+) TRAF2 (-) TRAF2 (+) TRAF2 (-) TRAF2 (+) TRAF2 AMP AMP AMP AMP AMP AMP TCGA Breast (n=494) TCGA Colon (n=240) TCGA Ovarian (n=426) 8 12 10 10 8 6 8 6 6 4 Expression Expression Expression 4 (Arbitrary units) (Arbitrary units) (Arbitrary units) 4 2 2 2 (-) TRAF2 (+) TRAF2 (-) TRAF2 (+) TRAF2 (-) TRAF2 (+) TRAF2 AMP AMP AMP AMP AMP AMP c kd KYSE30 RKO H2009 T47D SUM52 SW480 IGR39 NCI-H661 A2780 AU565 OV90 SW48 TRAF2 50 pTRAF2 (Ser11) 50 actin IKK actin Figure 1. TRAF2 is amplified in human cancers. (a) Copy number profiles at the 9q34 locus. Left panel, Significance of TRAF2 amplifications across 3131 cancer samples was determined by GISTIC (genomic identification of significant targets in cancer) and shown as q-values (false discovery rate-corrected significance of amplification frequency). Right panel, copy number profiles for 50 cancer samples harboring TRAF2 amplifications. Genomic location and the TRAF2 locus are indicated on the vertical axis and lineages on the horizontal axis are denoted by color. Copy number gain and loss are indicated as red and blue signals, respectively. (b) Scatterplots of TRAF2 mRNA expression in TRAF2- amplified or -nonamplified primary breast, ovarian and colon tumors in TCGA33–35 and cell lines in CCLE.43 These data are log2-transformed signal intensities with the median of each sample set denoted by a red line. (c) Immunoblot of TRAF2 and Ser11 phosphorylated TRAF2, and IKKE in 9q34-amplified (red) and copy neutral (black) cell lines. b-Actin is displayed as a loading control. Oncogene (2015) 209 – 216 & 2015 Macmillan Publishers Limited TRAF2 as NF-kB-activating oncogene in epithelial cancers RR Shen et al 211 cell lines derived from various lineages that either harbor or lack Table 1. FISH analysis of TRAF2 in cancer cell lines TRAF2 copy number gain and measured proliferation, apoptosis Cell line TRAF2 copy 9q34 9q34 and anchorage-independent growth (Supplementary Figure 3). number Amplification Rearrangement Twelve cell lines (KYSE510, KYSE30, RKO, EFO21, EFM19, IGROV1, LS513, SUM52, KYSE150, H2009, H1568 and T47D) with increased KYSE30 4.1 þþTRAF2 copy number exhibited decreased proliferative potential in RKO 3.8 þþa 7-day proliferation assay when we suppressed TRAF2 with two MDA-MB-453 3.7 þþdistinct TRAF2-specific short hairpin RNAs (shRNAs; Figure 2a and H2009 2.7 þþSupplementary Figure 3). In contrast, suppression of TRAF2 failed SUM52 2.6 þþto affect the proliferation of cell lines (A2780, LOVO, NCI-H661, MCF7 2.5 Àþ KYSE510 2.3 þþAU565, OV90 and SW48) that lacked TRAF2 amplification A2780 2.0 ÀÀ(Figure 2a). In long-term proliferation assays, we found that AU565 1.8 ÀÀsuppression of TRAF2 in cells harboring increased TRAF2 copy number (KYSE30, RKO, SUM52, KYSE150 and H2009) led to a mean Abbreviations: FISH, fluorescent in situ hybridization; TRAF2, tumor necrosis 41.6% decrease in the doubling time of such cells (Figure 2b). In factor receptor-associated factor 2. contrast, we failed to detect evidence of apoptosis after TRAF2 suppression (Supplementary Figure 4). Depletion of TRAF2 in three cell lines that exhibited delayed proliferative capacity (KYSE30, the targets of these amplifications.32 To validate this finding, we RKO and SUM52) also inhibited anchorage-independent growth performed fluorescent in situ hybridization on a panel of cancer (Figure 3a). We further found that TRAF2 suppression in three cell lines using a TRAF2-specific fosmid probe and confirmed 9q34-amplified cell lines, KYSE30, RKO and H2009 cells, inhibited increased TRAF2 copy number in six cancer cell lines classified by tumorigenesis in immunodeficient mice (Figure 3b).
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