DNAR-02. Nuclear potassium governs nuclear integrity and tumour growth in medulloblastoma

Abstract Potassium is the most abundant intracellular cation. Potassium flux across cell membranes is controlled by potassium channels. While cytoplasmic potassium has been extensively studied, very little is known about the function of potassium in the cell nucleus. Here, we discover that a nuclear potassium channel complex composed of KCNG1 and KCNB1 subunits is a regulator of nuclear potassium in medulloblastoma, the most common malignant pediatric brain tumour. Using genetically encoded potassium sensors, we show that KCNG1 regulates nuclear potassium level independently of cytoplasmic potassium level. KCNG1 knockdown alters the genomic architecture of medulloblastoma cells by stabilizing G-quadruplex DNA and inducing DNA damage. Ultimately, KCNG1 deficiency results in nuclear swelling, thereby compromising nuclear envelope integrity, promoting the formation of micronuclei, and inducing DNA spillage into the cytoplasm to activate the immune-stimulatory cGAS/STING pathway. Kcng1 knockout in a genetically engineered mouse model of medulloblastoma remodels the immune microenvironment, reduces tumour growth, and prolongs mouse survival. Altogether, we identified a potassium channel complex that regulates nuclear potassium to govern nuclear integrity, tumour immune microenvironment, and medulloblastoma growth. Our results demonstrate that targeting nuclear potassium can be leveraged to treat medulloblastoma.