New factor in the development of hereditary kidney cancer discovered

26.10.2022 | TopNews

(C) Lorea Valcarcel-Jimenez: Adjacent tumour on mouse kidney capsule

CECAD Scientists have identified the loss of the protein HIRA (histone cell cycle regulator) as a possible driving factor in a highly metastatic form of kidney cancer / study in ‘Science Advances’ opens up new perspectives for targeted therapies

Deletion of the HIRA protein promotes the proliferation and invasion of tumour cells in cell culture and animal models. That is the result of a research endeavour led by Alexander von Humboldt Professor Dr Christian Frezza at CECAD, the Cluster of Excellence at the University of Cologne. The hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is based on a change in the gene that produces the protein fumarate hydratase (FH). Fumarate hydratase is a cell protein that is significantly involved in energy production in cells. However, the mutation in the gene alone does not lead to the disease. Other factors such as the reduced production of HIRA are necessary for cancer to develop, which the scientists discovered with the help of CRISPR/Cas9 screening in cells. The research, which was started at the MRC Cancer Unit of Cambridge University and completed at CECAD in Cologne, has now been published in Science Advances under the title ‘HIRA loss transforms FH-deficient cells’.

‘Based on these new mechanistic findings, a model for HLRCC kidney tumours can be developed that opens up new perspectives for targeted therapies,’ said Dr Lorea Valcarcel, first author of the study.

In addition to the laboratory experiments, the scientists demonstrated a reduction in FH and HIRA proteins in affected HLRCC patients compared to samples from healthy individuals. Down-regulation of HIRA is also further confirmed by tumour biopsies from two patients compared to the normal surrounding tissue.

Thus, loss of HIRA activates the protein MYC, a known oncogene. Oncogenes are genes and proteins that positively influence tumour formation through its function and activation of other proteins.

Photo: The picture shows stained mouse tissue. Cells without HIRA develop tumours (purple) in proximity to the kidney (pink)

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Valcarcel-Jimenez L, Rogerson C, Yong C, Schmidt C, Yang M, Cremades-Rodelgo M, Harle V, Offord V, Wong K, Mora A, Speed A, Caraffini V, Tran MGB, Maher ER, Stewart GD, Vanharanta S, Adams DJ, Frezza C.  HIRA loss transforms FH-deficient cells. Science Advances 2022