KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming
- PMID: 35449309
- PMCID: PMC9969417
- DOI: 10.1038/s43018-022-00361-6
KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming
Abstract
Small cell lung cancer (SCLC) is notorious for its early and frequent metastases, which contribute to it as a recalcitrant malignancy. To understand the molecular mechanisms underlying SCLC metastasis, we generated SCLC mouse models with orthotopically transplanted genome-edited lung organoids and performed multiomics analyses. We found that a deficiency of KMT2C, a histone H3 lysine 4 methyltransferase frequently mutated in extensive-stage SCLC, promoted multiple-organ metastases in mice. Metastatic and KMT2C-deficient SCLC displayed both histone and DNA hypomethylation. Mechanistically, KMT2C directly regulated the expression of DNMT3A, a de novo DNA methyltransferase, through histone methylation. Forced DNMT3A expression restrained metastasis of KMT2C-deficient SCLC through repressing metastasis-promoting MEIS/HOX genes. Further, S-(5'-adenosyl)-L-methionine, the common cofactor of histone and DNA methyltransferases, inhibited SCLC metastasis. Thus, our study revealed a concerted epigenetic reprogramming of KMT2C- and DNMT3A-mediated histone and DNA hypomethylation underlying SCLC metastasis, which suggested a potential epigenetic therapeutic vulnerability.
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
Conflict of interest statement
Competing interests
The authors declare no competing interests.
Figures
![Extended Data Fig. 1 |](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9969417/bin/nihms-1870275-f0009.gif)
![Extended Data Fig. 2 |](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9969417/bin/nihms-1870275-f0010.gif)
![Extended Data Fig. 3 |](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9969417/bin/nihms-1870275-f0011.gif)
![Extended Data Fig. 4 |](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9969417/bin/nihms-1870275-f0012.gif)
![Extended Data Fig. 5 |](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9969417/bin/nihms-1870275-f0013.gif)
![Extended Data Fig. 6 |](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9969417/bin/nihms-1870275-f0014.gif)
![Extended Data Fig. 7 |](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9969417/bin/nihms-1870275-f0015.gif)
![Extended Data Fig. 8 |](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9969417/bin/nihms-1870275-f0016.gif)
![Extended Data Fig. 9 |](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9969417/bin/nihms-1870275-f0017.gif)
![Extended Data Fig. 10 |](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9969417/bin/nihms-1870275-f0018.gif)
![Fig. 1 |](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9969417/bin/nihms-1870275-f0001.gif)
![Fig. 2 |](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9969417/bin/nihms-1870275-f0002.gif)
![Fig. 3 |](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9969417/bin/nihms-1870275-f0003.gif)
![Fig. 4 |](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9969417/bin/nihms-1870275-f0004.gif)
![Fig. 5 |](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9969417/bin/nihms-1870275-f0005.gif)
![Fig. 6 |](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9969417/bin/nihms-1870275-f0006.gif)
![Fig. 7 |](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9969417/bin/nihms-1870275-f0007.gif)
![Fig. 8 |](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9969417/bin/nihms-1870275-f0008.gif)
Similar articles
-
Dnmt3a deficiency in the skin causes focal, canonical DNA hypomethylation and a cellular proliferation phenotype.Proc Natl Acad Sci U S A. 2021 Apr 20;118(16):e2022760118. doi: 10.1073/pnas.2022760118. Proc Natl Acad Sci U S A. 2021. PMID: 33846253 Free PMC article.
-
DNA methyltransferase 3A isoform b contributes to repressing E-cadherin through cooperation of DNA methylation and H3K27/H3K9 methylation in EMT-related metastasis of gastric cancer.Oncogene. 2018 Aug;37(32):4358-4371. doi: 10.1038/s41388-018-0285-1. Epub 2018 May 2. Oncogene. 2018. PMID: 29717263 Free PMC article.
-
Both combinatorial K4me0-K36me3 marks on sister histone H3s of a nucleosome are required for Dnmt3a-Dnmt3L mediated de novo DNA methylation.J Genet Genomics. 2020 Feb 20;47(2):105-114. doi: 10.1016/j.jgg.2019.12.006. Epub 2020 Feb 21. J Genet Genomics. 2020. PMID: 32173286
-
Targeting the epigenetic processes to enhance antitumor immunity in small cell lung cancer.Semin Cancer Biol. 2022 Nov;86(Pt 3):960-970. doi: 10.1016/j.semcancer.2022.02.018. Epub 2022 Feb 18. Semin Cancer Biol. 2022. PMID: 35189321 Review.
-
Alterations of Epigenetic Regulators in Pancreatic Cancer and Their Clinical Implications.Int J Mol Sci. 2016 Dec 19;17(12):2138. doi: 10.3390/ijms17122138. Int J Mol Sci. 2016. PMID: 27999365 Free PMC article. Review.
Cited by
-
Applied models and molecular characteristics of small cell lung cancer.Pathol Oncol Res. 2024 Apr 22;30:1611743. doi: 10.3389/pore.2024.1611743. eCollection 2024. Pathol Oncol Res. 2024. PMID: 38711976 Free PMC article. Review.
-
DNMT3A-mediated DNA methylation and transcription inhibition of FZD5 suppresses lung carcinogenesis.Heliyon. 2024 Apr 16;10(9):e29733. doi: 10.1016/j.heliyon.2024.e29733. eCollection 2024 May 15. Heliyon. 2024. PMID: 38707304 Free PMC article.
-
Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory.Nat Commun. 2024 Mar 19;15(1):2198. doi: 10.1038/s41467-024-46524-0. Nat Commun. 2024. PMID: 38503727 Free PMC article.
-
A pair of primary colorectal cancer-derived and corresponding synchronous liver metastasis-derived organoid cell lines.Aging (Albany NY). 2024 Feb 24;16(5):4396-4422. doi: 10.18632/aging.205595. Epub 2024 Feb 24. Aging (Albany NY). 2024. PMID: 38407980 Free PMC article.
-
Small cells - big issues: biological implications and preclinical advancements in small cell lung cancer.Mol Cancer. 2024 Feb 24;23(1):41. doi: 10.1186/s12943-024-01953-9. Mol Cancer. 2024. PMID: 38395864 Free PMC article. Review.
References
-
- Ramaswamy S, Ross KN, Lander ES & Golub TR A molecular signature of metastasis in primary solid tumors. Nat. Genet. 33, 49–54 (2003). - PubMed
Publication types
MeSH terms
Substances
Associated data
Grants and funding
LinkOut - more resources
Full Text Sources
Medical
Molecular Biology Databases