Role of Homeobox C Gene Cluster in Castration-Resistant Prostate Cancer
Abstract
Homeobox (HOX) genes play important roles in the anatomic development of an organism. The potency of these genes was exemplified in a famous experiment using fruit flies, where the modification of a single HOX gene caused the fly’s antennae to be replaced with legs. These HOX genes are active early in the development of an organism, but then are eternally turned off in adulthood. In cancer cells, these genes can be reactivated, triggering the immortality and pliability features associated with cancer cells, metastasis, and therapeutic resistance. Here, we propose an Idea Development Project to define the biologic role of several HOX genes in lethal prostate cancer (PCa)—specifically, metastatic and castration-resistant PCa (CRPC). There are four mammalian HOX gene clusters: HOXA, HOXB, HOXC, and HOXD. In humans, each cluster encodes approximately 10-15 genes. One specific cluster, the HOXC gene cluster, is generally off in normal prostate cells. As PCa develops, several HOXC genes get turned back on. One of them, HOXC6, has been shown to drive PCa cell growth and prevent PCa cell death. In fact, doctors measure HOXC6 mRNA, along with other genes, in the urine of men with a rising PSA in order to identify who requires a biopsy. So, if all of this is already known about HOXC genes, why do we want to study them further? Most studies on the HOXC genes cluster have been limited to localized prostate cancer. There was no information to suggest that they might be active in lethal PCa metastasis or therapeutic resistance. However, our preliminary studies discovered that several HOXC genes are turned back on when PCa cells convert from a castration-sensitive to a castration-resistant state. Even more interesting, we discovered several new gene products from the HOXC cluster that are generated by alternative splicing (the same mechanism that generates androgen-independent forms of the androgen receptor, like AR-V7). The project proposes three specific aims to study the biology of these and other HOXC genes in PCa metastasis and castration resistance. Aim 1: To define the role of HOXC genes in PCa metastasis and castration resistance. This aim proposes to alter the expression of individual HOXC genes in castration-sensitive and castration-resistant PCa cells and to apply live-cell imaging analysis to identify which HOXC genes drive cell proliferation, survival, migration, invasion, androgen responsiveness, and androgen dependence. We will also generate PCa tumors in mice to identify which HOXC genes drive tumor growth, metastasis, and castration resistance. Aim 2: To delineate the molecular pathways regulated by HOXC genes in CRPC. This aim proposes to alter the expression of individual HOXC genes in castration-sensitive and castration-resistant PCa cells and to apply whole transcriptome sequencing to define the genes and pathways regulated by each HOXC gene. Aim 3: To characterize the coding and non-coding nature of HOXC splice variants. This aim proposes molecular analyses to characterize the nature of alternatively spliced HOXC gene products. Ultimate Applicability of the Research: These studies directly address the PCRP Overarching Challenge to define the biology of lethal prostate cancer to reduce death. Exploratory and mechanistic research studies such as these are critical to reveal pathways and biomarkers that are associated with treatment response to discover mechanisms of resistance and new targets for therapy. These studies will rapidly bring important new knowledge to the PCa research community. What Type of Patients Will This Research Help? These studies are designed to help patients with advanced metastatic PCa. These studies could identify new pathways and biomarkers to predict whom will best respond to a therapy. They may also discover mechanisms of metastasis and castration resistance that could be targeted with future therapies. What is the Projected Time to Achieve a P
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110681
Entities
People
- Shawn E Lupold
Organizations
- Johns Hopkins University
- United States Army