Research Paper Volume 12, Issue 11 pp 10578—10593
CARM1 promotes non-small cell lung cancer progression through upregulating CCNE2 expression
- 1 Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
- 2 Department of Pharmacy, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
- 3 Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
- 4 Department of Radiotherapy Oncology, Nanjing Benq Medical Center, Nanjing 210019, China
Received: September 4, 2019 Accepted: April 7, 2020 Published: June 2, 2020https://doi.org/10.18632/aging.103280
How to Cite
Copyright © 2020 Wu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The underlying molecular mechanisms of tumorigenesis and progression of non-small cell lung cancer (NSCLC) are not yet fully elucidated. In the present study, in vitro functional dissections suggest that siRNA-mediated silencing of CCNE2 profoundly attenuated the proliferative and colony-formative abilities of NSCLC PC9 and HCC827 cells, while forced overexpression of CCNE2 significantly strengthened the proliferative and colony-formative capabilities of these cells. Intriguingly, by ChIP and luciferase reporter gene assays, we observed that CARM1 is recruited to the promoter regions of CCNE2 gene and acts as a transcriptional activator. Mechanically, the asymmetric di-methylation of H3R17me2a and H3R26me2a, as the catalytic substrates of CARM1, were highly enriched at the core promoter regions of CCNE2 gene, thereby activating the expression of CCNE2. In vitro and in vivo rescue experiments demonstrated that restoration of CCNE2 expression significantly abolished the CARM1 shRNA-mediated inhibition of cell proliferation, indicating that the oncogenic function of CARM1, at least partially, depended on the activation of CCNE2. Inhibition of CARM1 enzymatic activity could significantly repress CCNE2 expression in NSCLC cells. In addition, the expression of CARM1 was significantly elevated and positively correlated with CCNE2 levels in 20 cases of NSCLC patients. Both CARM1 and CCNE2 are highly associated with shorter 10-year overall survival of at a large cohort of 461 cases of NSCLC patients from the Kaplan-Meier plotter database. To summarize, these findings provide compelling evidence that CARM1 could promote NSCLC progression via activation of CCNE2, paving the way for future therapeutic strategies in NSCLC.