| Literature DB >> 35449309 |
Feifei Na1, Xiangyu Pan2, Jingyao Chen2, Xuelan Chen2, Manli Wang2, Pengliang Chi2, Liting You3, Lanxin Zhang2, Ailing Zhong2, Lei Zhao2, Siqi Dai2, Mengsha Zhang2, Yiyun Wang2, Bo Wang2, Jianan Zheng2, Yuying Wang2, Jing Xu2, Jian Wang2, Baohong Wu2, Mei Chen2, Hongyu Liu2, Jianxin Xue1, Meijuan Huang1, Youling Gong1, Jiang Zhu1, Lin Zhou1, Yan Zhang1, Min Yu1, Panwen Tian4, Mingyu Fan5, Zhenghao Lu1,6, Zhihong Xue1, Yinglan Zhao1, Hanshuo Yang2, Chengjian Zhao2, Yuan Wang2, Junhong Han2, Shengyong Yang2, Dan Xie2, Lu Chen2, Qian Zhong7, Musheng Zeng7, Scott W Lowe8,9, You Lu1, Yu Liu1, Yuquan Wei2, Chong Chen10,11.
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.Entities:
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Year: 2022 PMID： 35449309 DOI： 10.1038/s43018-022-00361-6
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347