Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma

Area of Science:

• Oncology
• Epigenetics
• Metabolic Pathways

Background:

• Histone methyltransferase KMT2D mutations are common in cancers, including melanoma.
• KMT2D's role as a tumor suppressor in melanoma is not fully understood.

Purpose of the Study:

• To investigate the function of KMT2D as a tumor suppressor in melanoma.
• To elucidate the mechanisms by which KMT2D loss affects melanoma tumorigenesis and metabolism.

Main Methods:

• In vivo epigenome-focused pooled RNAi screen.
• Genetically engineered mouse model (GEMM) with conditional, melanocyte-specific KMT2D deletion.
• Analysis of metabolic pathways, chromatin states (H3K4me1), and signaling pathways (IGF1R-AKT).

Main Results:

• KMT2D deficiency promotes melanoma tumorigenesis.
• KMT2D loss leads to reprogramming of glycolysis and increased glucose consumption.
• KMT2D loss reduces H3K4me1-marked active enhancers, repressing IGFBP5 and activating IGF1R-AKT signaling.
• Inhibition of glycolysis or IGF signaling reduces proliferation and tumorigenesis in KMT2D-deficient cells.

Conclusions:

• KMT2D acts as a potent tumor suppressor in melanoma.
• KMT2D loss promotes glycolysis via enhancer reprogramming and IGF1R-AKT activation.
• Targeting glycolysis or IGF signaling offers a therapeutic strategy for KMT2D-deficient melanomas.