CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300-mutated lymphomas.
Acetylation
/ drug effects
Animals
CREB-Binding Protein
/ genetics
Cell Line
Down-Regulation
/ genetics
E1A-Associated p300 Protein
/ genetics
Histone Acetyltransferases
/ metabolism
Lymphoma, Large B-Cell, Diffuse
/ genetics
Mice
Mice, Inbred NOD
Mice, SCID
Protein-Arginine N-Methyltransferases
/ antagonists & inhibitors
Synthetic Lethal Mutations
/ genetics
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
06
09
2019
accepted:
03
06
2020
revised:
02
06
2020
pubmed:
25
6
2020
medline:
5
1
2021
entrez:
25
6
2020
Statut:
ppublish
Résumé
Somatic mutations affecting CREBBP and EP300 are a hallmark of diffuse large B-cell lymphoma (DLBCL). These mutations are frequently monoallelic, within the histone acetyltransferase (HAT) domain and usually mutually exclusive, suggesting that they might affect a common pathway, and their residual WT expression is required for cell survival. Using in vitro and in vivo models, we found that inhibition of CARM1 activity (CARM1i) slows DLBCL growth, and that the levels of sensitivity are positively correlated with the CREBBP/EP300 mutation load. Conversely, treatment of DLBCLs that do not have CREBBP/EP300 mutations with CARM1i and a CBP/p300 inhibitor revealed a strong synergistic effect. Our mechanistic data show that CARM1i further reduces the HAT activity of CBP genome wide and downregulates CBP-target genes in DLBCL cells, resulting in a synthetic lethality that leverages the mutational status of CREBBP/EP300 as a biomarker for the use of small-molecule inhibitors of CARM1 in DLBCL and other cancers.
Identifiants
pubmed: 32576962
doi: 10.1038/s41375-020-0908-8
pii: 10.1038/s41375-020-0908-8
pmc: PMC7688486
mid: NIHMS1600952
doi:
Substances chimiques
Protein-Arginine N-Methyltransferases
EC 2.1.1.319
coactivator-associated arginine methyltransferase 1
EC 2.1.1.319
CREB-Binding Protein
EC 2.3.1.48
Crebbp protein, mouse
EC 2.3.1.48
E1A-Associated p300 Protein
EC 2.3.1.48
Ep300 protein, mouse
EC 2.3.1.48
Histone Acetyltransferases
EC 2.3.1.48
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
3269-3285Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM126421
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM137927
Pays : United States
Références
Al-Tourah AJ, Gill KK, Chhanabhai M, Hoskins PJ, Klasa RJ, Savage KJ, et al. Population-based analysis of incidence and outcome of transformed non-Hodgkin’s lymphoma. J Clin Oncol. 2008;26:5165–9.
pubmed: 18838711
doi: 10.1200/JCO.2008.16.0283
Guo L, Lin P, Xiong H, Tu S, Chen G. Molecular heterogeneity in diffuse large B-cell lymphoma and its implications in clinical diagnosis and treatment. Biochim Biophys Acta. 2018;1869:85–96.
Klein U, Dalla-Favera R. Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol. 2008;8:22–33.
pubmed: 18097447
doi: 10.1038/nri2217
MacLennan IC. Germinal centers. Annu Rev Immunol. 1994;12:117–39.
pubmed: 8011279
doi: 10.1146/annurev.iy.12.040194.001001
Victora GD, Nussenzweig MC. Germinal centers. Annu Rev Immunol. 2012;30:429–57.
pubmed: 22224772
doi: 10.1146/annurev-immunol-020711-075032
Green MR, Kihira S, Liu CL, Nair RV, Salari R, Gentles AJ, et al. Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. Proc Natl Acad Sci USA. 2015;112:E1116–25.
pubmed: 25713363
pmcid: 4364211
Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C, et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci USA. 2012;109:3879–84.
pubmed: 22343534
doi: 10.1073/pnas.1121343109
pmcid: 3309757
Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011;476:298–303.
pubmed: 21796119
pmcid: 3210554
doi: 10.1038/nature10351
Pasqualucci L, Dominguez-Sola D, Chiarenza A, Fabbri G, Grunn A, Trifonov V, et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature. 2011;471:189–95.
pubmed: 21390126
pmcid: 3271441
doi: 10.1038/nature09730
Pasqualucci L, Trifonov V, Fabbri G, Ma J, Rossi D, Chiarenza A, et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet. 2011;43:830–7.
pubmed: 21804550
pmcid: 3297422
doi: 10.1038/ng.892
Zhang J, Grubor V, Love CL, Banerjee A, Richards KL, Mieczkowski PA, et al. Genetic heterogeneity of diffuse large B-cell lymphoma. Proc Natl Acad Sci USA. 2013;110:1398–403.
pubmed: 23292937
doi: 10.1073/pnas.1205299110
pmcid: 3557051
Ceschin DG, Walia M, Wenk SS, Duboe C, Gaudon C, Xiao Y, et al. Methylation specifies distinct estrogen-induced binding site repertoires of CBP to chromatin. Genes Dev. 2011;25:1132–46.
pubmed: 21632823
pmcid: 3110952
doi: 10.1101/gad.619211
Chevillard-Briet M, Trouche D, Vandel L. Control of CBP co-activating activity by arginine methylation. EMBO J. 2002;21:5457–66.
pubmed: 12374746
pmcid: 129080
doi: 10.1093/emboj/cdf548
Lee YH, Coonrod SA, Kraus WL, Jelinek MA, Stallcup MR. Regulation of coactivator complex assembly and function by protein arginine methylation and demethylimination. Proc Natl Acad Sci USA. 2005;102:3611–6.
pubmed: 15731352
doi: 10.1073/pnas.0407159102
pmcid: 553305
Xu W, Chen H, Du K, Asahara H, Tini M, Emerson BM, et al. A transcriptional switch mediated by cofactor methylation. Science. 2001;294:2507–11.
pubmed: 11701890
doi: 10.1126/science.1065961
Bedford MT, Frankel A, Yaffe MB, Clarke S, Leder P, Richard S. Arginine methylation inhibits the binding of proline-rich ligands to Src homology 3, but not WW, domains. J Biol Chem. 2000;275:16030–6.
pubmed: 10748127
doi: 10.1074/jbc.M909368199
Yang Y, Lu Y, Espejo A, Wu J, Xu W, Liang S, et al. TDRD3 is an effector molecule for arginine-methylated histone marks. Mol Cell. 2010;40:1016–23.
pubmed: 21172665
pmcid: 3090733
doi: 10.1016/j.molcel.2010.11.024
Chen D, Ma H, Hong H, Koh SS, Huang SM, Schurter BT, et al. Regulation of transcription by a protein methyltransferase. Science. 1999;284:2174–7.
pubmed: 10381882
doi: 10.1126/science.284.5423.2174
Bedford MT, Richard S. Arginine methylation an emerging regulator of protein function. Mol Cell. 2005;18:263–72.
pubmed: 15866169
doi: 10.1016/j.molcel.2005.04.003
Lupien M, Eeckhoute J, Meyer CA, Krum SA, Rhodes DR, Liu XS, et al. Coactivator function defines the active estrogen receptor alpha cistrome. Mol Cell Biol. 2009;29:3413–23.
pubmed: 19364822
pmcid: 2698732
doi: 10.1128/MCB.00020-09
Yadav N, Lee J, Kim J, Shen J, Hu MC, Aldaz CM, et al. Specific protein methylation defects and gene expression perturbations in coactivator-associated arginine methyltransferase 1-deficient mice. Proc Natl Acad Sci USA. 2003;100:6464–8.
pubmed: 12756295
doi: 10.1073/pnas.1232272100
pmcid: 164469
Kim J, Lee J, Yadav N, Wu Q, Carter C, Richard S, et al. Loss of CARM1 results in hypomethylation of thymocyte cyclic AMP-regulated phosphoprotein and deregulated early T cell development. J Biol Chem. 2004;279:25339–44.
pubmed: 15096520
doi: 10.1074/jbc.M402544200
Yadav N, Cheng D, Richard S, Morel M, Iyer VR, Aldaz CM, et al. CARM1 promotes adipocyte differentiation by coactivating PPARgamma. EMBO Rep. 2008;9:193–8.
pubmed: 18188184
pmcid: 2246418
doi: 10.1038/sj.embor.7401151
Ito T, Yadav N, Lee J, Furumatsu T, Yamashita S, Yoshida K, et al. Arginine methyltransferase CARM1/PRMT4 regulates endochondral ossification. BMC Dev Biol. 2009;9:47.
pubmed: 19725955
pmcid: 2754437
doi: 10.1186/1471-213X-9-47
O’Brien KB, Alberich-Jorda M, Yadav N, Kocher O, Diruscio A, Ebralidze A, et al. CARM1 is required for proper control of proliferation and differentiation of pulmonary epithelial cells. Development. 2010;137:2147–56.
pubmed: 20530543
pmcid: 2882134
doi: 10.1242/dev.037150
Kim D, Lee J, Cheng D, Li J, Carter C, Richie E, et al. Enzymatic activity is required for the in vivo functions of CARM1. J Biol Chem. 2010;285:1147–52.
pubmed: 19897492
doi: 10.1074/jbc.M109.035865
Yang Y, Bedford MT. Protein arginine methyltransferases and cancer. Nat Rev Cancer. 2013;13:37–50.
pubmed: 23235912
doi: 10.1038/nrc3409
El Messaoudi S, Fabbrizio E, Rodriguez C, Chuchana P, Fauquier L, Cheng D, et al. Coactivator-associated arginine methyltransferase 1 (CARM1) is a positive regulator of the Cyclin E1 gene. Proc Natl Acad Sci USA. 2006;103:13351–6.
pubmed: 16938873
doi: 10.1073/pnas.0605692103
pmcid: 1569167
Hong H, Kao C, Jeng MH, Eble JN, Koch MO, Gardner TA, et al. Aberrant expression of CARM1, a transcriptional coactivator of androgen receptor, in the development of prostate carcinoma and androgen-independent status. Cancer. 2004;101:83–9.
pubmed: 15221992
doi: 10.1002/cncr.20327
Kim YR, Lee BK, Park RY, Nguyen NT, Bae JA, Kwon DD, et al. Differential CARM1 expression in prostate and colorectal cancers. BMC Cancer 2010;10:197.
pubmed: 20462455
pmcid: 2881889
doi: 10.1186/1471-2407-10-197
Osada S, Suzuki S, Yoshimi C, Matsumoto M, Shirai T, Takahashi S, et al. Elevated expression of coactivator-associated arginine methyltransferase 1 is associated with early hepatocarcinogenesis. Oncol Rep. 2013;30:1669–74.
pubmed: 23912631
doi: 10.3892/or.2013.2651
Mann M, Cortez V, Vadlamudi R. PELP1 oncogenic functions involve CARM1 regulation. Carcinogenesis. 2013;34:1468–75.
pubmed: 23486015
pmcid: 3697892
doi: 10.1093/carcin/bgt091
Wang L, Zhao Z, Meyer MB, Saha S, Yu M, Guo A, et al. CARM1 methylates chromatin remodeling factor BAF155 to enhance tumor progression and metastasis. Cancer Cell. 2014;25:21–36.
pubmed: 24434208
pmcid: 4004525
doi: 10.1016/j.ccr.2013.12.007
Karakashev S, Zhu H, Wu S, Yokoyama Y, Bitler BG, Park PH, et al. CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity. Nat Commun. 2018;9:631.
pubmed: 29434212
pmcid: 5809368
doi: 10.1038/s41467-018-03031-3
Bao J, Di Lorenzo A, Lin K, Lu Y, Zhong Y, Sebastian MM, et al. Mouse models of overexpression reveal distinct oncogenic roles for different type I protein arginine methyltransferases. Cancer Res. 2019;79:21–32.
pubmed: 30352814
doi: 10.1158/0008-5472.CAN-18-1995
Nakayama K, Szewczyk MM, Dela Sena C, Wu H, Dong A, Zeng H, et al. TP-064, a potent and selective small molecule inhibitor of PRMT4 for multiple myeloma. Oncotarget. 2018;9:18480–93.
pubmed: 29719619
pmcid: 5915086
doi: 10.18632/oncotarget.24883
Drew AE, Moradei O, Jacques SL, Rioux N, Boriack-Sjodin AP, Allain C, et al. Identification of a CARM1 inhibitor with potent in vitro and in vivo activity in preclinical models of multiple myeloma. Sci Rep. 2017;7:17993.
pubmed: 29269946
pmcid: 5740082
doi: 10.1038/s41598-017-18446-z
Greenblatt SM, Man N, Hamard PJ, Asai T, Karl D, Martinez C, et al. CARM1 is essential for myeloid leukemogenesis but dispensable for normal hematopoiesis. Cancer Cell. 2018;33:1111–27.e5.
pubmed: 29894694
pmcid: 6191185
doi: 10.1016/j.ccell.2018.05.007
Cheng D, Vemulapalli V, Lu Y, Shen J, Aoyagi S, Fry CJ, et al. CARM1 methylates MED12 to regulate its RNA-binding ability. Life Sci Alliance. 2018;1:e201800117.
pubmed: 30456381
pmcid: 6238599
doi: 10.26508/lsa.201800117
Lee J, Bedford MT. PABP1 identified as an arginine methyltransferase substrate using high-density protein arrays. EMBO Rep. 2002;3:268–73.
pubmed: 11850402
pmcid: 1084016
doi: 10.1093/embo-reports/kvf052
Zhang J, Vlasevska S, Wells VA, Nataraj S, Holmes AB, Duval R, et al. The CREBBP acetyltransferase is a haploinsufficient tumor suppressor in B-cell lymphoma. Cancer Discov. 2017;7:322–37.
pubmed: 28069569
pmcid: 5386396
doi: 10.1158/2159-8290.CD-16-1417
Creyghton MP, Cheng AW, Welstead GG, Kooistra T, Carey BW, Steine EJ, et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci USA. 2010;107:21931–6.
pubmed: 21106759
doi: 10.1073/pnas.1016071107
pmcid: 3003124
Andersen CL, Asmar F, Klausen T, Hasselbalch H, Gronbaek K. Somatic mutations of the CREBBP and EP300 genes affect response to histone deacetylase inhibition in malignant DLBCL clones. Leuk Res Rep. 2012;2:1–3.
pubmed: 24371765
pmcid: 3850379
Hashwah H, Schmid CA, Kasser S, Bertram K, Stelling A, Manz MG, et al. Inactivation of CREBBP expands the germinal center B cell compartment, down-regulates MHCII expression and promotes DLBCL growth. Proc Natl Acad Sci USA. 2017;114:9701–6.
pubmed: 28831000
doi: 10.1073/pnas.1619555114
pmcid: 5594639
Haery L, Lugo-Pico JG, Henry RA, Andrews AJ, Gilmore TD. Histone acetyltransferase-deficient p300 mutants in diffuse large B cell lymphoma have altered transcriptional regulatory activities and are required for optimal cell growth. Mol Cancer. 2014;13:29.
pubmed: 24529102
pmcid: 3930761
doi: 10.1186/1476-4598-13-29
Hammitzsch A, Tallant C, Fedorov O, O’Mahony A, Brennan PE, Hay DA, et al. CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses. Proc Natl Acad Sci USA. 2015;112:10768–73.
pubmed: 26261308
doi: 10.1073/pnas.1501956112
pmcid: 4553799
Han K, Jeng EE, Hess GT, Morgens DW, Li A, Bassik MC. Synergistic drug combinations for cancer identified in a CRISPR screen for pairwise genetic interactions. Nat Biotechnol. 2017;35:463–74.
pubmed: 28319085
pmcid: 5557292
doi: 10.1038/nbt.3834
Jiang Y, Ortega-Molina A, Geng H, Ying HY, Hatzi K, Parsa S, et al. CREBBP inactivation promotes the development of HDAC3-dependent lymphomas. Cancer Discov. 2017;7:38–53.
pubmed: 27733359
doi: 10.1158/2159-8290.CD-16-0975
Meyer SN, Scuoppo C, Vlasevska S, Bal E, Holmes AB, Holloman M, et al. Unique and shared epigenetic programs of the CREBBP and EP300 acetyltransferases in germinal center B cells reveal targetable dependencies in lymphoma. Immunity. 2019;51:535–47. e9.
pubmed: 31519498
pmcid: 7362711
doi: 10.1016/j.immuni.2019.08.006
Kasper LH, Fukuyama T, Biesen MA, Boussouar F, Tong C, de Pauw A, et al. Conditional knockout mice reveal distinct functions for the global transcriptional coactivators CBP and p300 in T-cell development. Mol Cell Biol. 2006;26:789–809.
pubmed: 16428436
pmcid: 1347027
doi: 10.1128/MCB.26.3.789-809.2006
Xu W, Fukuyama T, Ney PA, Wang D, Rehg J, Boyd K, et al. Global transcriptional coactivators CREB-binding protein and p300 are highly essential collectively but not individually in peripheral B cells. Blood. 2006;107:4407–16.
pubmed: 16424387
pmcid: 1895794
doi: 10.1182/blood-2005-08-3263
Chan-Penebre E, Kuplast KG, Majer CR, Boriack-Sjodin PA, Wigle TJ, Johnston LD, et al. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat Chem Biol. 2015;11:432–7.
pubmed: 25915199
doi: 10.1038/nchembio.1810
Kaushik S, Liu F, Veazey KJ, Gao G, Das P, Neves LF, et al. Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML. Leukemia 2018;32:499–509.
pubmed: 28663579
doi: 10.1038/leu.2017.206
Tarighat SS, Santhanam R, Frankhouser D, Radomska HS, Lai H, Anghelina M, et al. The dual epigenetic role of PRMT5 in acute myeloid leukemia: gene activation and repression via histone arginine methylation. Leukemia. 2016;30:789–99.
pubmed: 26536822
doi: 10.1038/leu.2015.308
Lu X, Fernando TM, Lossos C, Yusufova N, Liu F, Fontan L, et al. PRMT5 interacts with the BCL6 oncoprotein and is required for germinal center formation and lymphoma cell survival. Blood. 2018;132:2026–39.
pubmed: 30082494
pmcid: 6236466
doi: 10.1182/blood-2018-02-831438
George J, Lim JS, Jang SJ, Cun Y, Ozretic L, Kong G, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524:47–53.
pubmed: 26168399
pmcid: 4861069
doi: 10.1038/nature14664
Kishimoto M, Kohno T, Okudela K, Otsuka A, Sasaki H, Tanabe C, et al. Mutations and deletions of the CBP gene in human lung cancer. Clin Cancer Res. 2005;11:512–9.
pubmed: 15701835
Gui Y, Guo G, Huang Y, Hu X, Tang A, Gao S, et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat Genet. 2011;43:875–8.
pubmed: 21822268
pmcid: 5373841
doi: 10.1038/ng.907
Mullighan CG, Zhang J, Kasper LH, Lerach S, Payne-Turner D, Phillips LA, et al. CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature. 2011;471:235–9.
pubmed: 21390130
pmcid: 3076610
doi: 10.1038/nature09727
Okosun J, Bodor C, Wang J, Araf S, Yang CY, Pan C, et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet. 2014;46:176–81.
doi: 10.1038/ng.2856
pubmed: 24362818
Wilson BG, Helming KC, Wang X, Kim Y, Vazquez F, Jagani Z, et al. Residual complexes containing SMARCA2 (BRM) underlie the oncogenic drive of SMARCA4 (BRG1) mutation. Mol Cell Biol. 2014;34:1136–44.
pubmed: 24421395
pmcid: 3958034
doi: 10.1128/MCB.01372-13
Peifer M, Fernandez-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet. 2012;44:1104–10.
pubmed: 22941188
pmcid: 4915822
doi: 10.1038/ng.2396
So CK, Nie Y, Song Y, Yang GY, Chen S, Wei C, et al. Loss of heterozygosity and internal tandem duplication mutations of the CBP gene are frequent events in human esophageal squamous cell carcinoma. Clin Cancer Res. 2004;10:19–27.
pubmed: 14734447
doi: 10.1158/1078-0432.CCR-03-0160
Ogiwara H, Sasaki M, Mitachi T, Oike T, Higuchi S, Tominaga Y, et al. Targeting p300 addiction in CBP-Deficient cancers causes synthetic lethality by apoptotic cell death due to abrogation of MYC expression. Cancer Discov. 2016;6:430–45.
pubmed: 26603525
doi: 10.1158/2159-8290.CD-15-0754
Gao G, Zhang L, Villarreal OD, He W, Su D, Bedford E, et al. PRMT1 loss sensitizes cells to PRMT5 inhibition. Nucleic Acids Res. 2019;47:5038–48.
pubmed: 30916320
pmcid: 6547413
doi: 10.1093/nar/gkz200