Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers
Benjamin G Bitler, Katherine M Aird, Azat Garipov, Hua Li, Michael Amatangelo, Andrew V Kossenkov, David C Schultz, Qin Liu, Ie-Ming Shih, Jose R Conejo-Garcia, David W Speicher, Rugang Zhang, Benjamin G Bitler, Katherine M Aird, Azat Garipov, Hua Li, Michael Amatangelo, Andrew V Kossenkov, David C Schultz, Qin Liu, Ie-Ming Shih, Jose R Conejo-Garcia, David W Speicher, Rugang Zhang
Abstract
The gene encoding ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which currently have no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer cells and that ARID1A mutational status correlated with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct target of ARID1A and EZH2 that is upregulated by EZH2 inhibition and contributed to the observed synthetic lethality by inhibiting PI3K-AKT signaling. Importantly, EZH2 inhibition caused regression of ARID1A-mutated ovarian tumors in vivo. To our knowledge, this is the first data set to demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. Our data indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for cancers involving ARID1A mutations.
Figures
References
- Garraway LA, Lander ES. Lessons from the cancer genome. Cell. 2013;153:17–37.
- Lawrence MS, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature. 2014;505:495–501.
- Wilson BG, Roberts CW. SWI/SNF nucleosome remodellers and cancer. Nature reviews. Cancer. 2011;11:481–492.
- Wiegand KC, et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med. 2010;363:1532–1543.
- Jones S, et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science. 2010;330:228–231.
- Anglesio MS, et al. Type-specific cell line models for type-specific ovarian cancer research. PLoS One. 2013;8:e72162.
- Cao R, Zhang Y. The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Current opinion in genetics & development. 2004;14:155–164.
- Li H, Cai Q, Godwin AK, Zhang R. Enhancer of zeste homolog 2 promotes the proliferation and invasion of epithelial ovarian cancer cells. Molecular cancer research : MCR. 2010;8:1610–1618.
- McCabe MT, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012;492:108–112.
- Knutson SK, et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nature chemical biology. 2012;8:890–896.
- Qi W, et al. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proceedings of the National Academy of Sciences of the United States of America. 2012;109:21360–21365.
- Guan B, Gao M, Wu CH, Wang TL, Shih Ie M. Functional analysis of in-frame indel ARID1A mutations reveals new regulatory mechanisms of its tumor suppressor functions. Neoplasia. 2012;14:986–993.
- Yamada KM, Cukierman E. Modeling tissue morphogenesis and cancer in 3D. Cell. 2007;130:601–610.
- Jenuwein T. The epigenetic magic of histone lysine methylation. FEBS J. 2006;273:3121–3135.
- Guan B, Wang TL, Shih Ie M. ARID1A, a factor that promotes formation of SWI/SNF-mediated chromatin remodeling, is a tumor suppressor in gynecologic cancers. Cancer research. 2011;71:6718–6727.
- Konze KD, et al. An orally bioavailable chemical probe of the Lysine Methyltransferases EZH2 and EZH1. ACS chemical biology. 2013;8:1324–1334.
- Kennison JA, Tamkun JW. Dosage-dependent modifiers of polycomb and antennapedia mutations in Drosophila. Proceedings of the National Academy of Sciences of the United States of America. 1988;85:8136–8140.
- Li H, et al. ALDH1A1 is a novel EZH2 target gene in epithelial ovarian cancer identified by genome-wide approaches. Cancer Prev Res (Phila) 2012;5:484–491.
- Stany MP, et al. Identification of novel therapeutic targets in microdissected clear cell ovarian cancers. PLoS One. 2011;6:e21121.
- He X, et al. PIK3IP1, a negative regulator of PI3K, suppresses the development of hepatocellular carcinoma. Cancer research. 2008;68:5591–5598.
- Zhu Z, et al. PI3K is negatively regulated by PIK3IP1, a novel p110 interacting protein. Biochemical and biophysical research communications. 2007;358:66–72.
- Yamamoto S, Tsuda H, Takano M, Tamai S, Matsubara O. Loss of ARID1A protein expression occurs as an early event in ovarian clear-cell carcinoma development and frequently coexists with PIK3CA mutations. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2012;25:615–624.
- Samartzis EP, Noske A, Dedes KJ, Fink D, Imesch P. ARID1A mutations and PI3K/AKT pathway alterations in endometriosis and endometriosis-associated ovarian carcinomas. International journal of molecular sciences. 2013;14:18824–18849.
- Chandler RL, et al. ARID1a-DNA interactions are required for promoter occupancy by SWI/SNF. Molecular and cellular biology. 2013;33:265–280.
- Davidovich C, Zheng L, Goodrich KJ, Cech TR. Promiscuous RNA binding by Polycomb repressive complex 2. Nature structural & molecular biology. 2013;20:1250–1257.
- Cho KR, Shih Ie M. Ovarian cancer. Annual review of pathology. 2009;4:287–313.
- Helming KC, et al. ARID1B is a specific vulnerability in ARID1A-mutant cancers. Nature medicine. 2014;20:251–254.
- Wilson BG, et al. Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer cell. 2010;18:316–328.
- Knutson SK, et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proceedings of the National Academy of Sciences of the United States of America. 2013;110:7922–7927.
- Hargreaves DC, Crabtree GR. ATP-dependent chromatin remodeling: genetics, genomics and mechanisms. Cell research. 2011;21:396–420.
- Debnath J, Muthuswamy SK, Brugge JS. Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods. 2003;30:256–268.
- Ye X, et al. Downregulation of Wnt signaling is a trigger for formation of facultative heterochromatin and onset of cell senescence in primary human cells. Mol Cell. 2007;27:183–196.
- Tu Z, et al. Oncogenic RAS regulates BRIP1 expression to induce dissociation of BRCA1 from chromatin, inhibit DNA repair, and promote senescence. Developmental cell. 2011;21:1077–1091.
- Zhang S. A comprehensive evaluation of SAM, the SAM R-package and a simple modification to improve its performance. BMC bioinformatics. 2007;8:230.
- Storey JD, Tibshirani R. Statistical significance for genomewide studies. Proceedings of the National Academy of Sciences of the United States of America. 2003;100:9440–9445.
- Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nature methods. 2012;9:357–359.
- Kim D, et al. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome biology. 2013;14:R36.
- Bitler BG, et al. Wnt5a suppresses epithelial ovarian cancer by promoting cellular senescence. Cancer research. 2011;71:6184–6194.
- Li H, et al. SUZ12 promotes human epithelial ovarian cancer by suppressing apoptosis via silencing HRK. Mol Cancer Res. 2012;10:1462–1472.
Source: PubMed