Targeting Methylation-Mediated Mitotic Fragility in ccRCC
Abstract
Clear cell renal cell carcinoma (ccRCC) is defined by two co-occurring events, deletion of chromosome 3p and gain of chromosome 5q. The loss of genetic material on 3p results in the loss of one copy of SETD2 and PBRM1 whereas NSD1 on chromosome 5q is amplified. To date there is no common nuclear function that explains how loss/gain of these traditionally nuclear proteins (SETD2, PBRM1, and NSD1) drive cancer formation. In exciting new data, we show these proteins are required to preserve the integrity of the cell division process. ccRCC is not a tumor that undergoes rapid cell division early in disease course and therefore therapies targeting this process have not been extensively studied. Our data now reveal that it is the quality of the cell division process itself and not how often the cell divides that is of importance to the cancer cell. We have previously shown SETD2 is essential for normal cell division, and in cells that have lost both copies of SETD2, cell division is impaired. So how do cells handle cell division in ccRCC where the cells have lost one copy of SETD2? We propose two novel ways in which the cell compensates for loss of SETD2 and detail how putting a wrench in an already impaired process of cell division early in disease progression can eliminate the cancer cells. These studies highlight the rationale and exploit a susceptibility in cancer cells, which our data uncover for the first time with applicability to both sporadic ccRCC and VHL disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210508
Entities
People
- Ruhee Dere
Organizations
- Baylor College of Medicine
- United States Army