KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming

Na, Feifei, Pan, Xiangyu, Chen, Jingyao, Chen, Xuelan, Wang, Manli, Chi, Pengliang, You, Liting, Zhang, Lanxin, Zhong, Ailing, Zhao, Lei, Dai, Siqi, Zhang, Mengsha, Wang, Yiyun, Wang, Bo, Zheng, Jianan, Wang, Yuying, Xu, Jing, Wang, Jian, Wu, Baohong, Chen, Mei, Liu, Hongyu, Xue, Jianxin, Huang, Meijuan, Gong, Youling, Zhu, Jiang, Zhou, Lin, Zhang, Yan, Yu, Min, Tian, Panwen, Fan, Mingyu, Lu, Zhenghao, Xue, Zhihong, Zhao, Yinglan, Yang, Hanshuo, Zhao, Chengjian, Wang, Yuan, Han, Junhong, Yang, Shengyong, Xie, Dan, Chen, Lu, Zhong, Qian, Zeng, Musheng, Lowe, Scott W, Lu, You, Liu, Yu, Wei, Yuquan, Chen, Chong (April 2022) KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming. Nature Cancer. ISSN 2662-1347

URL: https://www.ncbi.nlm.nih.gov/pubmed/35449309
DOI: 10.1038/s43018-022-00361-6

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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > epigenetics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > epigenetics
diseases & disorders > cancer > metastasis
diseases & disorders > cancer > cancer types > small cell lung cancer
CSHL Authors:
Communities: CSHL labs > Lowe lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 21 April 2022
Date Deposited: 02 May 2022 20:00
Last Modified: 02 May 2022 20:00
URI: https://repository.cshl.edu/id/eprint/40599

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