Clear cell renal cell carcinoma (ccRCC) is defined by two co-occurring genetic events, deletion of the short arm of chromosome 3p and gain of chromosome 5q, which results in loss of one copy of VHL, SETD2, PBRM1 and gain of NSD1. A subsequent deletion of the other copy of VHL drives oncogenesis. To date there is no common nuclear function that explains how these traditionally nuclear proteins drive cancer formation.

In exciting new data, we show an intersection of these proteins at structures involved in cell division (at mitotic spindles). ccRCC is not a tumor that is highly proliferative (undergoing lots of cell division) and therefore therapies targeting cell division have not been exte...

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Clear cell renal cell carcinoma (ccRCC) is defined by two co-occurring genetic events, deletion of the short arm of chromosome 3p and gain of chromosome 5q, which results in loss of one copy of VHL, SETD2, PBRM1 and gain of NSD1. A subsequent deletion of the other copy of VHL drives oncogenesis. To date there is no common nuclear function that explains how these traditionally nuclear proteins drive cancer formation.

In exciting new data, we show an intersection of these proteins at structures involved in cell division (at mitotic spindles). ccRCC is not a tumor that is highly proliferative (undergoing lots of cell division) and therefore therapies targeting cell division have not been extensively studied. Our data now reveal that it is not the number of cell divisions per se that is crucial but the quality or integrity of the process itself. We have previously shown SETD2 is essential for normal cell division, and in cells that have lost SETD2 cell division is impaired.

So how do cells handle cell division in ccRCC where the cells loose one copy of SETD2? We hypothesize RCC cells compensate for this loss of SETD2 by increasing levels of Aurora Kinase A (AURKA). We have recently found VHL targets AURKA for degradation. We hypothesize that high AURKA resulting from VHL loss, increases the activity of the remaining SETD2 during cell division, enabling cells to divide. Another way that cells compensate for SETD2 loss is to increase NSD1 levels. SETD2 writes a "methyl" mark on tubulin which makes up the mitotic spindle.

We propose that NSD1 writes the first mark allowing SETD2 to add the final mark on tubulin, which promotes normal cell division. Thus, we strategize that both signaling nodes can be therapeutically targeted to drive faulty cell division which should result in cell death. Therefore, the proposed studies provide an innovative approach to exploit a susceptibility in ccRCC, with applicability to both sporadic ccRCC and VHL disease.

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