The Role of BMI1-Associated lncRNAs in Advanced Prostate Cancer
Abstract
Just like many other cancers, the development of prostate cancer is caused by the impairments in many cellular processes and molecular pathways, such as those involved in cell survival and the DNA repair system. These pathways are particularly important as, if the system fails to repair DNA that is damaged by drugs, radiation, UV, or other harmful factors and unable to control the growth of these DNA-damaged cells in the body, it will lead to the development of cancer. The Polycomb Group (PcG) proteins, long non-coding RNAs (lncRNAs), are RNAs that cannot be translated to proteins or only can be translated to oligo-peptides), and other components play a significant role in regulating cell growth, death, and DNA damage repair. Reports have demonstrated that dysregulation in PcG proteins and lncRNAs are involved in prostate cancer initiation, progression, and castration-resistance. We have discovered that BMI1, a member of the PcG family of proteins, is overexpressed in prostate cancer, particularly in aggressive and/or metastatic prostate cancers. Metastatic form of cancer is dangerous as it can spread to secondary organs and reduces the survival rate in cancer patients. Importantly, prostate cancer patients with high BMI1 levels have worse clinical outcomes compared to patients with low BMI1 expression. Furthermore, a significant body of evidence indicates that dysregulated BMI1 and other PcG proteins, along with the hormone-regulated androgen receptor (AR), are contributed to prostate cancer development and progression. This proposal outlines our plans to explore how BMI1 regulates lncRNAs by modulating lncRNAs’ expression levels or forming functional complexes with lncRNAs during prostate cancer progression. In this project, we will characterize the functions of these novel BMI1-regulated lncRNAs and BMI1-binding lncRNAs in prostate cancer. In addition to that, we will elucidate how these lncRNAs work together with BMI1 to enhance the prostate cancer tumor growth, drug resistance, and metastasis. Finally, we will test whether the inhibition of these lncRNAs by specifically depleting lncRNAs in tumor cells using anti-sense oligos (ASOs) could potentially have any therapeutic efficacy to kill prostate cancer cells or repress the cancer cell/tumor growth in preclinical mouse models. Once this project is completed, it will yield new insights into the cellular mechanisms of prostate cancer development, including disease initiation and progression. If our hypotheses are correct, our data will provide a strong rationale to develop therapies targeting BMI1-binding lncRNAs or BMI1-activated lncRNAs and potentially reduce the mortality of prostate cancer by improving treatment efficacy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010504
Entities
People
- Qi Cao
Organizations
- Northwestern University
- United States Army