KMT2C Loss Promotes Small Cell Lung Cancer Metastasis through DNMT3A-mediated Epigenetic Reprogramming

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 multi-omics analyses. We found that loss of KMT2C, an H3K4 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 new epigenetic therapeutic vulnerability. Small cell lung cancer (SCLC) is a neuroendocrine lung malignancy characterized with rapid progress and heavy metastasis. To understand the molecular mechanisms underlying its unique pathology, we developed a new strategy to rapidly generate driver-defined primary and orthotopical murine SCLC models with gene-edited lung organoids. Single cell transcriptome analyses of primary and metastatic SCLC revealed a metastasis trajectory associated with dysregulated epigenetic programs. Disruption of KMT2C, an H3K4 methyltransferase frequently mutated in human SCLC of extensive stage, promoted the growth and metastasis of SCLC in mice. Interestingly, KMT2C loss resulted in significantly reduced DNA methylation through directly regulating the expression of DNMT3A. Ectopically expressing DNMT3A or treatment with S-adenosyl methionine repressed the metastasis of KMT2C-deficient SCLC. These epigenetic reprogramming exaggerated SCLC metastasis partially through upregulating Meis/Hox genes. Taken together, our study revealed an unprecedented synergistic histone and DNA hypomethylation in SCLC.