HIRA loss transforms FH-deficient cells.

Area of Science:

• Cellular biology
• Cancer research
• Biochemistry

Background:

• Fumarate hydratase (FH) is a mitochondrial enzyme crucial for the tricarboxylic acid (TCA) cycle.
• Germline mutations in FH cause hereditary leiomyomatosis and renal cell carcinoma (HLRCC), a syndrome linked to aggressive kidney cancer.
• FH-deficient cells in mice develop kidney cysts, not carcinomas, indicating tumor-suppressive mechanisms that are not fully understood.

Purpose of the Study:

• To identify genes that, when lost, promote the proliferation of FH-deficient cells.
• To understand the mechanisms by which FH-deficient cells overcome tumor suppression.
• To uncover potential therapeutic targets for HLRCC.

Main Methods:

• Genome-wide CRISPR-Cas9 screening was employed to identify genes essential for the proliferation of FH-deficient cells.
• In vitro and in vivo assays were used to assess the impact of gene ablation on cell proliferation and invasion.
• Molecular analyses were performed to investigate the mechanistic link between gene loss, MYC activation, and nucleotide metabolism.

Main Results:

• Depletion of the histone cell cycle regulator (HIRA) significantly enhances the proliferation and invasion of FH-deficient cells.
• Loss of HIRA activates MYC and its target genes, leading to increased nucleotide metabolism in FH-deficient cells.
• This effect is independent of HIRA's canonical histone chaperone activity.

Conclusions:

• HIRA acts as a critical suppressor of proliferation and invasion in FH-deficient cells.
• The loss of HIRA promotes HLRCC tumorigenesis by activating MYC-driven nucleotide metabolism.
• Targeting HIRA or MYC pathway could be a potential therapeutic strategy for HLRCC patients.