Histone

Gene

Metastasis

EZH2

Methyltransferase

Biology

Epigenetics

Cancer research

DNA methylation

Epigenomics

Cancer epigenetics

Genetics

Histone methylation

Methylation

Histone methyltransferase

Histone H3

Cell

Cancer

Gene expression

Reprogramming

Nature Cancer

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. Na et al. identify KMT2C deficiency as a driver of small cell lung cancer metastasis and demonstrate that it leads to epigenetic reprogramming through histone and DNA hypomethylation by upregulating DNMT3A.

KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming