KMT2D Deficiency Impairs Super-Enhancers to Confer a Glycolytic Vulnerability in Lung Cancer

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• Epigenetic modifiers often have loss-of-function mutations in lung cancer, but their tumor-suppressive functions are not well understood.
• KMT2D (also known as MLL4), a histone methyltransferase, is frequently inactivated in lung cancer, suggesting a tumor suppressor role.

Purpose of the Study:

• To investigate the tumor-suppressive role of KMT2D in lung cancer.
• To explore the therapeutic implications of KMT2D inactivation in lung cancer.

Main Methods:

• Utilized a mouse model with lung-specific Kmt2d loss to study tumorigenesis.
• Analyzed the impact of KMT2D deficiency on gene expression and epigenomic landscapes.
• Assessed the efficacy of glycolysis inhibitors in human lung cancer cells with KMT2D mutations.

Main Results:

• Lung-specific Kmt2d loss accelerated lung tumor formation in mice and enhanced pro-tumorigenic pathways, notably glycolysis.
• KMT2D inactivation led to widespread disruption of super-enhancer/enhancer epigenomic marks.
• Loss of Kmt2d reduced PER2 expression, a repressor of circadian rhythm, which in turn influenced glycolytic gene expression.

Conclusions:

• KMT2D functions as a tumor suppressor in the lung.
• KMT2D deficiency creates a therapeutic vulnerability, making lung cancer cells susceptible to glycolysis inhibitors.