PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies

Nature

Volumn 514, Issue 7521, 2014, Pages 247-251

  De Raedt, Thomas ^a,b,c   Beert, Eline ^d   Pasmant, Eric ^e,f   Luscan, Armelle ^e,f   Brems, Hilde ^d   Ortonne, Nicolas ^e,f   Helin, Kristian ^g,h,i   Hornick, Jason L ^a   Mautner, Victor ^j   Kehrer Sawatzki, Hildegard ^k   Clapp, Wade ^l   Bradner, James ^b,m   Vidaud, Michel ^e,f   Upadhyaya, Meena ⁿ   Legius, Eric ^d,o   Cichowski, Karen ^a,b,c  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c DANA FARBER HARVARD CANCER CENTER   (United States)

^d UNIVERSITY OF LEUVEN   (Belgium)

^e INSERM   (France)

^f Assistance Publique Hôpitaux de Paris ^*  (France)

^g UNIVERSITY OF COPENHAGEN   (Denmark)

^h UNIVERSITY OF COPENHAGEN   (Denmark)

ⁱ University of Copenhagen   (Denmark)

^j UNIVERSITY MEDICAL CENTER HAMBURG EPPENDORF   (Germany)

^k UNIVERSITY OF ULM   (Germany)

^l INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

^m DANA FARBER CANCER INSTITUTE   (United States)

ⁿ CARDIFF UNIVERSITY   (United Kingdom)

^o UNIVERSITY HOSPITALS LEUVEN   (Belgium)

more..

Author keywords

[No Author keywords available]

Indexed keywords

(+) JQ1 COMPOUND; (+)-JQ1 COMPOUND; AZEPINE DERIVATIVE; BRD4 PROTEIN, HUMAN; MITOGEN ACTIVATED PROTEIN KINASE KINASE; NEUROFIBROMIN; NUCLEAR PROTEIN; POLYCOMB REPRESSIVE COMPLEX 2; RAS PROTEIN; SUZ12 PROTEIN, HUMAN; SUZ12 PROTEIN, MOUSE; TRANSCRIPTION FACTOR; TRIAZOLE DERIVATIVE; TUMOR SUPPRESSOR PROTEIN;

ANIMAL; ARTICLE; CELL DEATH; CHROMATIN; DISEASE MODEL; DRUG ANTAGONISM; DRUG EFFECT; GENE EXPRESSION REGULATION; GENETIC EPIGENESIS; GENETIC TRANSCRIPTION; GENETICS; GLIOMA; HUMAN; MELANOMA; METABOLISM; MOUSE; NEOPLASM; NERVE SHEATH TUMOR; PATHOLOGY;

ANIMALS; AZEPINES; CELL DEATH; CHROMATIN; DISEASE MODELS, ANIMAL; EPIGENESIS, GENETIC; GENE EXPRESSION REGULATION, NEOPLASTIC; GLIOMA; HUMANS; MELANOMA; MICE; MITOGEN-ACTIVATED PROTEIN KINASE KINASES; NEOPLASMS; NERVE SHEATH NEOPLASMS; NEUROFIBROMIN 1; NUCLEAR PROTEINS; POLYCOMB REPRESSIVE COMPLEX 2; RAS PROTEINS; TRANSCRIPTION FACTORS; TRANSCRIPTION, GENETIC; TRIAZOLES; TUMOR SUPPRESSOR PROTEINS;

EID: 84908321120     PISSN: 00280836     EISSN: 14764687     Source Type: Journal    
DOI: 10.1038/nature13561     Document Type: Article

References (33)

1. Sauvageau, M. & Sauvageau, G. Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. Cell Stem Cell 7, 299-313 (2010).
2. Ernst, T. et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nature Genet. 42, 722-726 (2010).
3. Zhang, J. et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481, 157-163 (2012).
4. Maertens, O.&Cichowski, K. An expanding role for RASGTPase activating proteins (RAS GAPs) in cancer. Adv. Biol. Regul. 55, 1-14 (2014).
5. Downward, J. Targeting RAS signalling pathways in cancer therapy. Nature Rev. Cancer 3, 11-22 (2003).
6. Shaw, A. T. et al. Sprouty-2 regulates oncogenic K-ras in lung development and tumorigenesis. Genes Dev. 21, 694-707 (2007).
7. Feldser, D. M. et al. Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature 468, 572-575 (2010).
8. Junttila, M. R. et al. Selective activation of p53-mediated tumour suppression in high-grade tumours. Nature 468, 567-571 (2010).
9. Xu, J. et al. Dominant role of oncogene dosage and absence of tumor suppressor activity in Nras-driven hematopoietic transformation. Cancer Discov. 3, 993-1001 (2013).
10. McLaughlin, S. K. et al. The RasGAP gene, RASAL2, is a tumor and metastasis suppressor. Cancer Cell 24, 365-378 (2013).
11. Min, J. et al. An oncogene-tumor suppressor cascade drivesmetastatic prostate cancer by coordinately activating Ras andnuclear factor-κB. Nature Med. 16, 286-294(2010).
12. De Raedt, T. et al. Genomic organization and evolution of the NF1 microdeletion region. Genomics 84, 346-360 (2004).
13. Lopez-Correa, C. et al. Recombination hotspot in NF1 microdeletion patients. Hum. Mol. Genet. 10, 1387-1392 (2001).
14. De Raedt, T. et al. Elevated risk for MPNST in NF1 microdeletion patients. Am. J. Hum. Genet. 72, 1288-1292 (2003).
15. Mautner, V. F. et al. Clinical characterisation of 29 neurofibromatosis type-1 patients with molecularly ascertained 1.4 Mb type-1 NF1 deletions. J. Med. Genet. 47, 623-630 (2010).
16. Beroukhim, R. et al. Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma. Proc Natl Acad Sci USA 104, 20007-20012 (2007).
17. McGillicuddy, L. T. et al. Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis. Cancer Cell 16, 44-54 (2009).
18. Cichowski, K. et al. Mouse models of tumor development in neurofibromatosis type 1. Science 286, 2172-2176 (1999).
19. Legius, E. et al. TP53 mutations are frequent in malignant NF1 tumors. Genes Chromosom. Cancer 10, 250-255 (1994).
20. Beert, E. et al. Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors. Genes Chromosom. Cancer 50, 1021-1032 (2011).
21. Pasini, D. et al. Characterization of an antagonistic switch between histone H3 lysine 27 methylation and acetylation in the transcriptional regulation of Polycomb group target genes. Nucleic Acids Res. 38, 4958-4969 (2010).
22. Filippakopoulos, P. et al. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell 149, 214-231 (2012).
23. Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 468, 1067-1073 (2010).
24. Widemann, B. C. Current status of sporadic and neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors. Curr. Oncol. Rep. 11, 322-328 (2009).
25. Delmore, J. E. et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146, 904-917 (2011).
26. Puissant, A. et al. Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 3, 308-323 (2013).
27. Johannessen, C. M. et al. TORC1 is essential for NF1-associated malignancies. Curr. Biol. 18, 56-62 (2008).
28. De Raedt, T. et al. Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors. Cancer Cell 20, 400-413 (2011).
29. Chang, T. et al. Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice. J. Clin. Invest. 123, 335-339 (2013).
30. Jessen, W. J. et al. MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors. J. Clin. Invest. 123, 340-347 (2013).
31. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545-15550 (2005).
32. Jacks, T. et al. Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nature Genet. 7, 353-361 (1994).
33. Pasini, D., Bracken, A. P., Jensen, M. R., Lazzerini Denchi, E. & Helin, K. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J. 23, 4061-4071 (2004).