Characterizing the Roles of Alternative Polyadenylation During Prostate Cancer Progression
Abstract
Prostate cancer is the most common cancer in men worldwide. Metastatic castration-resistant prostate cancer (mCRPC), the lethal form of prostate cancer, is causing the second most cancer-related mortality in American men. The anti-androgen is one of the principal treatments for mCRPC patients and has demonstrated improved survival in men with mCRPC in recent clinical trials. The majority of patients benefit from treatment with this strategy. However, disease progression is inevitable, and little is known about mechanisms that contribute to clinical anti-androgen resistance. Meanwhile, neuroendocrine prostate cancer (NEPC) is the most virulent form of prostate cancer. Importantly, the recent work demonstrates NEPC is increasing in frequency and is present in approximately 17% of mCRPC patient tumors. Using the next-generation sequencing technology, the recent efforts have revealed the recurrent genomics alterations and aberrant gene expression in the prostate cancer progression into lethal forms. However, prostate cancer is a heterogeneous disease, and advanced prostate cancer remains incurable. To improve prostate cancer diagnosis, prognosis and response to treatment, it is necessary to identify alternative molecular characteristics of prostate cancer, such as alternative polyadenylation (APA), that will open a new way to the personalized therapeutic strategy. APA enables the same gene to have multiple 3 UTR ends and affects more than 70% of human genes. Using different polyadenylation sites within a gene, APA can create transcripts with diverse 3’ UTRs that have distinct protein-coding regions or contain different cis-regulatory elements, like miRNA binding sites, leading to altered function and stability. Accumulating evidence has indicated that APA is playing important roles in cancers. In prostate cancer, specifically, APA contributes to androgen receptor (AR) splicing to generate constitutively active AR variant 7 (AR-V7), which promotes the progression of CRPC. AR-V7 has been established as a biomarker for the resistance to AR-targeting therapies. However, the underlying mechanism governing differential APA usage for genes like AR-V7 is unknown. A better mechanistic understanding of the APA landscape and how it governs key cancer hallmarks in mCRPC may lead to new insights about how to treat this disease. By bringing together computational and experimental biologists, this proposal will address the Overarching Challenge to define the biology of lethal prostate cancer to reduce death. 1. We will perform the most comprehensive analysis of APA across ~1,400 publicly available prostate cancer RNA-seq samples, including primary tumors, mCRPC, enzalutamide-resistance CRPC, and NEPC. 2. By employing single-cell RNA-seq of mCRPC, we will perform the first single-cell level APA profiling and APA regulator prediction. 3. We will reveal signature APA genes and novel APA regulators governing differential APA usages in prostate cancer metastasis, anti-androgen resistance, and alternative differentiation programs like NEPC. We anticipate that this proposal will establish the APA as a new platform for prostate cancer research. Specifically, this research has the potential to: 1. Provide biomarkers that capture novel mechanisms of anti-androgen resistance to inform treatment decisions. 2. Provide novel biomarkers of APA genes in NEPC diagnosis. 3. Determine the APA regulators that drive the development of lethal prostate cancer like CRPC and NEPC through the APA mechanism in both in vitro and in vivo preclinical models, which may serve as therapeutic targets.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110539
Entities
People
- Zheng Xia
Organizations
- Oregon Health & Science University
- United States Army