TY - JOUR
T1 - HIRA loss transforms FH-deficient cells
AU - Valcarcel-Jimenez, Lorea
AU - Rogerson, Connor
AU - Yong, Cissy
AU - Schmidt, Christina
AU - Yang, Ming
AU - Cremades-Rodelgo, Monica
AU - Harle, Victoria
AU - Offord, Victoria
AU - Wong, Kim
AU - Mora, Ariane
AU - Speed, Alyson
AU - Caraffini, Veronica
AU - Tran, Maxine Gia Binh
AU - Maher, Eamonn R
AU - Stewart, Grant D
AU - Vanharanta, Sakari
AU - Adams, David J
AU - Frezza, Christian
PY - 2022/10/21
Y1 - 2022/10/21
N2 - 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 FH 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 Fh1-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 Fh1-deficient cells. We found that the depletion of the histone cell cycle regulator (HIRA) enhances proliferation and invasion of Fh1-deficient cells in vitro and in vivo. Mechanistically, Hira loss activates MYC and its target genes, increasing nucleotide metabolism specifically in Fh1-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.
AB - 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 FH 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 Fh1-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 Fh1-deficient cells. We found that the depletion of the histone cell cycle regulator (HIRA) enhances proliferation and invasion of Fh1-deficient cells in vitro and in vivo. Mechanistically, Hira loss activates MYC and its target genes, increasing nucleotide metabolism specifically in Fh1-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.
UR - https://www.science.org/doi/10.1126/sciadv.abq8297
U2 - 10.1126/sciadv.abq8297
DO - 10.1126/sciadv.abq8297
M3 - Article
C2 - 36269833
SN - 2375-2548
VL - 8
JO - Science Advances
JF - Science Advances
IS - 42
M1 - eabq8297
ER -