The Role of Lysine Methyltransferase KMT2D in Head and Neck Cancer

Head and neck squamous carcinoma (HNSC) is the one of the most frequent cancers worldwide, with 890,000 cases diagnosed and 450,000 deaths each year. The majority of HNSC patients presents with advanced tumors and lymph node metastasis. Recurrence after treatment is a frequent clinical problem, and the five year survival rate for HNSC patients is low. Genomic studies have revealed that HNSC is a heterogeneous disease at both the molecular and cellular levels. The most frequently mutated epigenetic modifier in HNSC is the lysine methyltransferase KMT2D. Missense mutations and deletions inactivate KMT2D function in HNSC. KMT2D expression predicted tumor recurrence in HNSC. KMT2D protein catalyzes methylation of histone H3K4 resulting in activation of target genes. Despite the frequency of KMT2D inactivation in HNSC, the role of this enzyme in progression of these cancers is unclear. We hypothesized that KMT2D regulates target genes that promote tumor progression in HNSC. These target genes regulate the immune response in HNSC. We demonstrated that KMT2D loss of heterozygosity resulted in reduced lymph node metastasis and tumor growth in HNSC due to decreased proliferation. KMT2D+/f HNSC is characterized by decreased macrophage gene expression signature. Reduced expression of the macrophage chemotaxis protein CCL2 resulted in reduced lymph node metastasis and tumor growth in HNSC. Reduced cellular proliferation correlated with slow growth in CCL2-/- HNSC.