The NFIB/CARM1 Partnership is a Driver in Preclinical Models of Small Cell Lung Cancer

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Jan 23

PMID 36690626

Authors

Guozhen Gao

Simone Hausmann

Natasha M Flores

Ana Morales Benitez

Jianjun Shen

Xiaojie Yang

Maria D Person

Sitaram Gayatri

Donghang Cheng

Yue Lu

Bin Liu

Pawel K Mazur

Mark T Bedford

Affiliations

Soon will be listed here.

Abstract

The coactivator associated arginine methyltransferase (CARM1) promotes transcription, as its name implies. It does so by modifying histones and chromatin bound proteins. We identified nuclear factor I B (NFIB) as a CARM1 substrate and show that this transcription factor utilizes CARM1 as a coactivator. Biochemical studies reveal that tripartite motif 29 (TRIM29) is an effector molecule for methylated NFIB. Importantly, NFIB harbors both oncogenic and metastatic activities, and is often overexpressed in small cell lung cancer (SCLC). Here, we explore the possibility that CARM1 methylation of NFIB is important for its transforming activity. Using a SCLC mouse model, we show that both CARM1 and the CARM1 methylation site on NFIB are critical for the rapid onset of SCLC. Furthermore, CARM1 and methylated NFIB are responsible for maintaining similar open chromatin states in tumors. Together, these findings suggest that CARM1 might be a therapeutic target for SCLC.

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References

Gobius I, Morcom L, Suarez R, Bunt J, Bukshpun P, Reardon W . Astroglial-Mediated Remodeling of the Interhemispheric Midline Is Required for the Formation of the Corpus Callosum. Cell Rep. 2016; 17(3):735-747. PMC: 5094913. DOI: 10.1016/j.celrep.2016.09.033. View

Yang Y, Lu Y, Espejo A, Wu J, Xu W, Liang S . TDRD3 is an effector molecule for arginine-methylated histone marks. Mol Cell. 2010; 40(6):1016-23. PMC: 3090733. DOI: 10.1016/j.molcel.2010.11.024. View

Na F, Pan X, Chen J, Chen X, Wang M, Chi P . KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming. Nat Cancer. 2022; 3(6):753-767. PMC: 9969417. DOI: 10.1038/s43018-022-00361-6. View

Hsu Y, Osinski J, Campbell C, David Litwack E, Wang D, Liu S . Mesenchymal nuclear factor I B regulates cell proliferation and epithelial differentiation during lung maturation. Dev Biol. 2011; 354(2):242-52. PMC: 3098902. DOI: 10.1016/j.ydbio.2011.04.002. View

Woodard R, Anderson M, Dynan W . Nuclear extracts lacking DNA-dependent protein kinase are deficient in multiple round transcription. J Biol Chem. 1998; 274(1):478-85. DOI: 10.1074/jbc.274.1.478. View

Brun M, Coles J, Monckton E, Glubrecht D, Bisgrove D, Godbout R . Nuclear factor I regulates brain fatty acid-binding protein and glial fibrillary acidic protein gene expression in malignant glioma cell lines. J Mol Biol. 2009; 391(2):282-300. DOI: 10.1016/j.jmb.2009.06.041. View

Schaffer B, Park K, Yiu G, Conklin J, Lin C, Burkhart D . Loss of p130 accelerates tumor development in a mouse model for human small-cell lung carcinoma. Cancer Res. 2010; 70(10):3877-83. PMC: 2873158. DOI: 10.1158/0008-5472.CAN-09-4228. View

Denny S, Yang D, Chuang C, Brady J, Lim J, Gruner B . Nfib Promotes Metastasis through a Widespread Increase in Chromatin Accessibility. Cell. 2016; 166(2):328-342. PMC: 5004630. DOI: 10.1016/j.cell.2016.05.052. View

Yan C, Higgins P . Drugging the undruggable: transcription therapy for cancer. Biochim Biophys Acta. 2012; 1835(1):76-85. PMC: 3529832. DOI: 10.1016/j.bbcan.2012.11.002. View

10.

Chen D, Ma H, Hong H, Koh S, Huang S, Schurter B . Regulation of transcription by a protein methyltransferase. Science. 1999; 284(5423):2174-7. DOI: 10.1126/science.284.5423.2174. View

11.

Cheng D, Cote J, Shaaban S, Bedford M . The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing. Mol Cell. 2007; 25(1):71-83. DOI: 10.1016/j.molcel.2006.11.019. View

12.

Masuda Y, Takahashi H, Hatakeyama S . TRIM29 regulates the p63-mediated pathway in cervical cancer cells. Biochim Biophys Acta. 2015; 1853(10 Pt A):2296-305. DOI: 10.1016/j.bbamcr.2015.05.035. View

13.

Guo A, Gu H, Zhou J, Mulhern D, Wang Y, Lee K . Immunoaffinity enrichment and mass spectrometry analysis of protein methylation. Mol Cell Proteomics. 2013; 13(1):372-87. PMC: 3879628. DOI: 10.1074/mcp.O113.027870. View

14.

Guccione E, Richard S . The regulation, functions and clinical relevance of arginine methylation. Nat Rev Mol Cell Biol. 2019; 20(10):642-657. DOI: 10.1038/s41580-019-0155-x. View

15.

Yang D, Denny S, Greenside P, Chaikovsky A, Brady J, Ouadah Y . Intertumoral Heterogeneity in SCLC Is Influenced by the Cell Type of Origin. Cancer Discov. 2018; 8(10):1316-1331. PMC: 6195211. DOI: 10.1158/2159-8290.CD-17-0987. View

16.

Vu L, Perna F, Wang L, Voza F, Figueroa M, Tempst P . PRMT4 blocks myeloid differentiation by assembling a methyl-RUNX1-dependent repressor complex. Cell Rep. 2013; 5(6):1625-38. PMC: 4073674. DOI: 10.1016/j.celrep.2013.11.025. View

17.

Lajoie M, Hsu Y, Gronostajski R, Bailey T . An overlapping set of genes is regulated by both NFIB and the glucocorticoid receptor during lung maturation. BMC Genomics. 2014; 15:231. PMC: 4023408. DOI: 10.1186/1471-2164-15-231. View

18.

Gayatri S, Bedford M . Readers of histone methylarginine marks. Biochim Biophys Acta. 2014; 1839(8):702-10. PMC: 4099268. DOI: 10.1016/j.bbagrm.2014.02.015. View

19.

Veazey K, Cheng D, Lin K, Villarreal O, Gao G, Perez-Oquendo M . CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300-mutated lymphomas. Leukemia. 2020; 34(12):3269-3285. PMC: 7688486. DOI: 10.1038/s41375-020-0908-8. View

20.

Tang Z, Cui Q, Dong Q, Xu K, Wang E . Ataxia-telangiectasia group D complementing gene (ATDC) upregulates matrix metalloproteinase 9 (MMP-9) to promote lung cancer cell invasion by activating ERK and JNK pathways. Tumour Biol. 2013; 34(5):2835-42. DOI: 10.1007/s13277-013-0843-7. View