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Publication Spotlight: Deficiency of KMT2C is Mutated in Extensive SCLC, Promotes Multiple-Organ Metastases

In a recent Nature Cancer publication, Na, Feifei, et al., found that a deficiency of KMT2C, a histone H3 lysine 4 methyltransferase frequently mutated in extensive-stage Small cell lung cancer (SCLC), promoted multiple-organ metastases in mice using our Histone H3 Mouse Monoclonal Antibody [3-C4] (EM30605).

Small cell lung cancer is an aggressive form of lung cancer that most commonly occurs in smokers. It usually starts in the bronchi and grows very quickly, creating large tumors and metastasizing throughout the body. 

According to Na, Feifei, et al., despite metastasis being the leading cause of death for individuals with cancer, so far, there have been very few driver mutations identified for metastasis. They found that KMT2C deficiency is a major driver of SCLC metastasis and that KMT2C is frequently mutated in many human cancers and acts as a tumor suppressor gene (TSG) in SCLC. The functional roles of KMT2C in metastasis were validated with multiple ex vivo and in vivo models. Their work not only validates KMT2C as a TSG in SCLC but also reveals KMT2C as a driver for metastasis. Several other KMT2C-related epigenetic regulators, such as KMT2D and KDM6A, are also frequently mutated in SCLC.

KMT2C is an H3K4 methyltransferase and is associated with gene activation31; therefore, it is expected that downregulation of the majority of downstream genes of KMT2C in acute myeloid leukemia with KMT2C loss is observed. However, in SCLC, the researchers found that KMT2C deficiency not only represses the expression of metastasis-associated TSGs but also upregulates metastasis-promoting genes, such as MEIS2 and several HOXB genes that are overexpressed in human SCLC. 

Na, Feifei, et al., show that DNA hypomethylation, mediated by the downregulation of DNMT3A, a direct target of KMT2C, underlies the activation of these prometastatic genes. Their study provides an example of how an epigenetic regulator coordinates the expression of genes with opposite functions (here pro- and antimetastasis) through concerted epigenetic reprogramming and their findings demonstrate prometastatic histone and DNA hypomethylation could provide treatment options for SCLC.

Cited Antibodies:

Histone H3 Mouse Monoclonal Antibody [3-C4] (EM30605)


Related Antibody Collections:




Na, Feifei, et al. "KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming." Nature Cancer (2022): 1-15.

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