Defining the Consequence of CHD1 Loss on Transcriptional Regulation and Therapeutic Response
Abstract
During my time as a graduate student and now as a postdoctoral fellow, I have been privileged to have the ability to immerse myself in the field of cancer biology. This bird?s eye view of different cancer types has made it abundantly clear that while most other cancers have identified several molecular targets that have been utilized for successful therapeutic intervention, prostate cancer (PCa) has lagged behind. Fortunately, research has taken a significant step forward in identifying novel molecular targets to thwart cancer growth with the aid of genome-wide sequencing. Our group (as well as others) has sequenced a large number of primary tumors and discovered unique molecular subclasses of PCa, each with its own specific signature and molecular profile. One of the most common molecular subclasses is characterized by a genomic deletion of the chromatin remodeling factor CHD1, which represents between 10%-20% of all primary PCas. Interestingly, this deletion event is not shared with any other cancer type, suggesting that the loss of CHD1 is uniquely specific to PCa and could be developed as a pharmacological target. Thus, this award will support my goal of identifying new targets for therapeutic intervention by uncovering the consequences of CHD1 loss on gene expression programs responsible for PCa initiation and progression. PCa is highly dependent upon the action of the androgen receptor (AR), the protein responsible for prostate cell growth and survival at all stages of disease. AR is a transcription factor that is activated by binding to androgens (e.g., testosterone). Activation results in the in AR binding to DNA where it induces the expression of a specific set of target genes required for prostate development and growth. Importantly, a critical step in the process of prostate tumorigenesis is the rewiring of AR, wherein AR is redirected away from its normal target genes, and instead promotes the expression of genes associated with tumor growth and survival. One well-established mechanism for this reprogramming can be seen in the ERG-fusion positive subclass of PCa, which inappropriately expresses the transcription factor ERG. In this context, ERG can physically bind to DNA and AR and direct it to novel sites on DNA, where it forces AR to promote expression of pro-oncogenic genes unique to this subclass of PCa. This signature has been established in a multitude of clinical samples and is distinct from all other subtypes of PCa, including those characterized by CHD1 loss. Thus, while ERG induction has been established as a key event in the rewiring of AR during tumor formation, the mechanisms that alter AR binding in the other subtypes remain unclear. CHD1 is a member of the chromatin remodeling family whose primary function is to open up DNA to allow for essential proteins to bind and promote gene expression. Several studies have demonstrated that CHD1 is recruited to genes that are highly expressed and is required to maintain cell survival and growth. Interestingly however, our preliminary data suggest that CHD1 functions differently in a prostate-specific setting. For the first time, we demonstrate that in a prostate-specific background, (1) CHD1 directs where AR binds to DNA, (2) cells that lack CHD1 still require AR for growth and survival, (3) loss of CHD1 does not decrease cell growth or survival, and (4) the absence of CHD1 does not result in lower levels of gene expression. We thus hypothesize that loss of CHD1 represents a specific mechanism though which AR is reprogrammed to promote tumor formation and growth. Given that the clinical signatures of this subtype of cancer are very distinct from the others, it is likely that identification of the genes that AR regulates in CHD1 deficient tumors will nominate novel pathways that can be targeted to limit growth of this aggressive tumor class. To validate this hypothesis, we will be using both cell culture and animal model systems. We e
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710137
Entities
People
- Michael Augello
Organizations
- United States Army
- Weill Cornell Medicine