The Role of EZH2-ADAR1 Axis in Advanced Prostate Cancer
Abstract
Prostate cancer is one of the most common cancer types and ranks as the second leading cause of cancer-related death among American men. Although therapeutic strategies such as androgen deprivation therapy (ADT) has been successfully used to treat prostate cancer, the majority of patients still eventually relapse and result in dismal outcomes. To this end, it is of paramount importance to identify novel viable targets to help patients diagnosed with lethal prostate cancer go back to normal. RNA editing is a widely conserved modification which could change the specific nucleotide of RNA transcript from one to another. The most prevalent type of RNA editing in humans is adenosine-to-inosine (A-to-I), which is catalyzed primarily by an enzyme named adenosine deaminases acting on RNA-1 (ADAR1). In addition to the RNA editing function, which is mainly restricted in the cell nucleus, ADAR1 protein could also translocate to the cytoplasm under stress and protect its interacting mRNAs from degradation. Cumulative evidence suggests that aberrant ADAR1 expression and A-to-I RNA editing profiles are implicated in prostate cancer, but the underlying mechanism remains unknown. Therefore, understanding the link between ADAR1 and prostate cancer and uncovering the mechanism by which ADAR1 is modulated in response to oncogenic signals during prostate cancer progression will contribute to define the biology of prostate cancer progression to lethal prostate cancer to reduce death. Enhancer of zeste homolog 2 (EZH2) is a well-known enzymatic protein that has histone methyltransferase activity. Elevated expression of EZH2 has been reported in many solid tumors including prostate cancer. The unique roles of EZH2 in promoting cancer progression and metastasis make it a potential therapeutic target for cancer treatment. However, scientists found that targeting the enzymatic activity of EZH2 alone is ineffective in treating EZH2-dependent solid tumors. Instead, emerging findings including ours support the notion that EZH2 could promote cancer development through multiple ways that do not rely on its enzymatic activity. Hence, deeply investigating the multifaceted tumorigenic functions of EZH2 will shed new light on understanding the etiology of cancer. Here, we report for the first time that, EZH2 plays novel enzymatic-independent roles in regulation of A-to-I RNA editing and RNA stability via targeting ADAR1. Our preliminary data suggested that EZH2 could directly interact with ADAR1 to modulate its preference to choose editing substrates. Consequently, the global A-to-I editing pattern in prostate cancer cells is largely re-shaped due to the upregulation of EZH2 to facilitate cancer initiation and progression. More importantly, we further suggested that EZH2 could keep the ADAR1 proteins stay inside the nucleus by promoting the translation of Transportin-1 (TRN1), a protein that is responsible for the transportation of ADAR1 from cytoplasm to nucleus. Therefore, depletion of EZH2 in prostate cancer cells will lead to the accumulation of cytoplasmic ADAR1 in prostate cancer cells, which subsequently prevents a number of ADAR1-bound mRNAs from degradation. Among the group of EZH2-mediated mRNAs, we identified Ataxia-Telangiectasia Mutated (ATM), which encodes a protein that helps cancer cells develop therapeutic resistance. Accordingly, combinational targeting of EZH2 and ATM using specific inhibitors could achieve a synergistic effect in killing prostate cancer cells. In this application, we will build upon our novel preliminary findings to understand the role of EZH2 in modulation of ADAR1 during the progression of prostate cancer. Our proposed study will not only enrich our knowledge on the molecular mechanism by which EZH2 drives prostate cancer, but also shed new light on the development of novel therapeutics to benefit prostate patients. To be specific, although the EZH2-targeting strategy has been utilize
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310661
Entities
People
- Yi Yang
Organizations
- Northwestern University
- United States Army