<i>HIRA</i> loss transforms <i>FH</i>-deficient cells.

Abstract

Fumarate hydratase (FH) is a mitochondrial enzyme that catalyzes the reversible hydration of fumarate to malate in the tricarboxylic acid (TCA) cycle. Germline mutations of <i>FH</i> lead to hereditary leiomyomatosis and renal cell carcinoma (HLRCC), a cancer syndrome characterized by a highly aggressive form of renal cancer. Although HLRCC tumors metastasize rapidly, FH-deficient mice develop premalignant cysts in the kidneys, rather than carcinomas. How <i>Fh1</i>-deficient cells overcome these tumor-suppressive events during transformation is unknown. Here, we perform a genome-wide CRISPR-Cas9 screen to identify genes that, when ablated, enhance the proliferation of <i>Fh1</i>-deficient cells. We found that the depletion of the histone cell cycle regulator (HIRA) enhances proliferation and invasion of <i>Fh1</i>-deficient cells in vitro and in vivo. Mechanistically, <i>Hira</i> loss activates MYC and its target genes, increasing nucleotide metabolism specifically in <i>Fh1</i>-deficient cells, independent of its histone chaperone activity. These results are instrumental for understanding mechanisms of tumorigenesis in HLRCC and the development of targeted treatments for patients.