Xuerui Yang’s Group Elucidated the Tumor-promoting Function of lncRNA NEAT1 in Prostate Cancer Cells2018-06-12 11:44:01
The long noncoding RNA nuclear enriched abundant transcript 1 (NEAT1) has been shown to regulate multiple cancer-related cellular activities including cell proliferation, apoptosis, and migration. However, the detailed mechanisms have not been fully elucidated. Xuerui Yang’s group in the School of Life Sciences at Tsinghua University has been using an integrative strategy to solve this problem. Their efforts led to the discovery of a transcriptional regulation circuit from CDC5L to AGRN, which is regulated by NEAT1 and responsible for the tumor-promoting function of NEAT1 in prostate cancer cells. These findings have been recently published in Cancer Research (Oncogenic properties of NEAT1 in prostate cancer cells depend on the CDC5L-AGRN transcriptional regulation circuit).
NEAT1 is an essential component of the paraspeckle, which is a nuclear speckle near the cell nucleolus. Substantial abnormalities of NEAT1 have been observed frequently in various cancer-related contexts. However, the exact role of NEAT1 in tumorigenesis was still debated. A team led by Dr. Xuerui Yang confirmed that NEAT1 is essential for the proliferation and tumorigenesis of the castration-resistant prostate cancer (CRPC) cell lines. They showed that knocking down NEAT1 resulted in significant DNA damage and suppression of cell proliferation and tumor growth.
Mechanistic investigations for many lncRNAs has been challenging and the studies remain limited, partly due to lack of prior knowledge and difficulties in generating plausible hypotheses to start with. Therefore, comprehensive functional surveys of the lncRNAs with existing data would be of high value for honing in on specific lncRNAs, generating testable hypotheses, and guiding the mechanistic studies. In Xuerui Yang’s lab, to elucidate the machinery responsible for the essential function of NEAT1 in prostate cancer cells, they applied an integrative data-mining strategy to identify potential transcription factors whose transcriptional activity depends on the level of NEAT1. This analysis based on transcriptome profiling data from about 500 prostate tumors in The Cancer Genome Atlas (TCGA) yielded a series of known transcription factors and other DNA binding proteins, including CDC5L, which has been shown to bind directly to NEAT1.
Guided by the data-mining results, experimental studies in Xuerui Yang’s lab confirmed the regulation of CDC5L by NEAT1 and identified the target gene of CDC5L, AGRN, which was modulated by NEAT1. Finally, the team proved that this transcriptional regulatory circuit, NEAT1-CDC5L-AGRN, is essential for proper tumor cell growth, and repression of the pathway causes DNA damage and potent arrest of the cell cycle and proliferation.
In summary, Xuerui Yang’s group has revealed, for the first time, a specific transcriptional regulation circuit modulated by lncRNA NEAT1, which in turn facilitates DNA integrity and promotes proliferation of prostate cancer cells. Success of this research project is a demonstration of the unique advantage of combining sophisticated data-mining and detailed experimental investigation in generating plausible hypothesis and uncovering detailed mechanisms.
PhD student Xin Li in Xuerui Yang’s lab is the first author of the paper. The study was supported by the national key research and development program, Precision Medicine Project, the National Natural Science Foundation of China, the Tsinghua University Initiative Scientific Research Program, the Tsinghua–Peking Joint Center for Life Sciences, and the 1000 talent program (Youth Category). The study also received supports from the Platforms of Genome Sequencing, High-Performance Computing, shRNA Library, and Cell Imaging & Function of the National Protein Science Facility (Beijing), the Lab Animal Center at Tsinghua University, and the Flow Cytometry Core Facility of Center of Biomedical Analysis at Tsinghua University.
Figure: Working model of the NEAT1-CDC5L-AGRN circuit in prostate cancer cells.