| Authors: |
Na, F.; Pan, X.; Chen, J.; Chen, X.; Wang, M.; Chi, P.; You, L.; Zhang, L.; Zhong, A.; Zhao, L.; Dai, S.; Zhang, M.; Wang, Y.; Wang, B.; Zheng, J.; Wang, Y.; Xu, J.; Wang, J.; Wu, B.; Chen, M.; Liu, H.; Xue, J.; Huang, M.; Gong, Y.; Zhu, J.; Zhou, L.; Zhang, Y.; Yu, M.; Tian, P.; Fan, M.; Lu, Z.; Xue, Z.; Zhao, Y.; Yang, H.; Zhao, C.; Wang, Y.; Han, J.; Yang, S.; Xie, D.; Chen, L.; Zhong, Q.; Zeng, M.; Lowe, S. W.; Lu, Y.; Liu, Y.; Wei, Y.; Chen, C. |
| 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. |
