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
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.
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