Targeting a Combined VHL and 3p Chromatin Remodeler Deficit in Renal Cell Carcinoma
Abstract
Loss of the short arm of chromosome 3 (3p loss) is a hallmark of renal cell cancer. There are several genes that are lost because of loss of this piece of DNA. Most importantly, both copies of the tumor suppressor gene von Hippel Lindau (VHL) are lost (the first copy is lost due to loss of 3p and the other is usually mutated and will not function either) along with one copy each of three genes -- SETD2, PBRM1, and BAP1 -- that function in the nucleus to remodel the DNA, altering accessibility for other factors that also need to work on DNA. Most studies focus on this nuclear function of the so called chromatin remodelers (SETD2, PBRM1, and BAP1), although there is no known common function where all three gene products participate together in the nucleus. More recently our work and others has identified that all three chromatin remodelers (SETD2, PBRM1, and BAP1) also function outside the nucleus on structures called microtubules that form a mesh-like network that gives the cell its characteristic shape. Any irregularities in this organized meshwork, especially when cells are dividing, has catastrophic results for the cell and could result in cell death. When the short arm of chromosome 3 is deleted, and therefore one copy of SETD2, PBRM1, and BAP1 and two copies of VHL are lost, we do not know if the remaining copy of the SETD2, PBRM1, and BAP1 genes produce enough gene products to perform all the functions in the cell as normal. This proposal tackles this very important question of what happens when the cell loses one copy of these genes, not only to its nuclear function but to its function on the microtubules. This is especially important for any targeted therapy as interventions should be aimed at both functions and not only the nuclear function, although this has yet to be addressed in the field. We are proposing to evaluate novel targets that we will identify in this proposal and validate the same using patient-derived kidney cancer cells for their capability to target both functions of the chromatin remodelers. These studies are hugely important as they will address questions directly relevant to human kidney cancer using an innovative model that we have developed to specifically study these complex gene interactions and in which we can identify novel targets for intervention. We will identify interventions based on a deep understanding of the molecular mechanisms that drive cancer formation and progression. The findings from our research will be directly relevant not only to renal cancer but VHL disease and other cancers where the short arm of chromosome 3 is lost.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210475
Entities
People
- Ruhee Dere
Organizations
- Baylor College of Medicine
- United States Army