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

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 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE161570 | GEO | 2022/02/23

REPOSITORIES: GEO

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