Epigenetic Regulation of NAMPT by NAMPT-ASDrives Metastatic Progression in Triple-Negative Breast Cancer
Authors: Ning Zhang
Qifeng Yang
Xiaolong Wang
Yiran Liang
Guohong Hu
Haiyang Guo
Peng Su
Tong Chen
Wenjing Zhao
Bing Chen
Yuting Sang
Jiashu Zhang
Yi Duan
Xiaojin Song
Zhaojian Liu
Lijuan Wang
Ying Liu
Hanwen Zhang
Yaming Li
Journal: Cancer Research (2019)
Discipline: CLINICAL MEDICINE
Keywords: Triple-negative breast cancer; TNBC; long noncoding RNAs; lncRNA; molecular mechanisms
Affiliations: Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China., Department of Pathology, Qilu Hospital of Shandong University, Ji'nan, Shandong, China., Pathology Tissue Bank, Qilu Hospital of Shandong University, Ji'nan, Shandong, China., Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada., Department of Cell Biology, Shandong University School of Medicine, Jinan, China., The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, Shanghai, China., Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China. .

Abstract:  Triple-negative breast cancer (TNBC) is highly heterogeneous and has a poor prognosis. It is therefore important to identify the underlying molecular mechanisms in order to develop novel therapeutic strategies. Although emerging research has revealed long noncoding RNAs (lncRNA) as vital to carcinogenesis and cancer progression, their functional involvement in TNBC has not been well defined. In this study, we utilized the The Cancer Genome Atlas (TCGA) database and analyzed clinical samples to show that the long noncoding antisense transcript of nicotinamide phosphoribosyltransferase (NAMPT), NAMPT-AS, is upregulated in TNBC and is associated with poor prognosis, lymph node involvement, metastasis, and advanced stage. NAMPT-AS was cotranscribed with NAMPT from a bidirectional promoter, where the distributions of H3K4me3 and H3K27Ac chromatin modifications were enriched based on ENCODE and FANTOM5, suggesting the potential enhancer-RNA characteristics of NAMPT-AS. NAMPT-AS epigenetically regulated the expression of NAMPT in two divergent ways: NAMPT-AS recruited POU2F2 to activate the transcription of NAMPT, and NAMPT-AS acted as a competing endogenous RNA to rescue NAMPT degradation from miR-548b-3p. NAMPT-AS/NAMPT promoted tumor progression and regulated autophagy through the mTOR pathway in vitro and in vivo. In a cohort of 480 breast cancer patients, NAMPT was associated with breast cancer-specific survival and overall survival. These results demonstrate that NAMPT-AS is an oncogenic lncRNA in TNBC that epigenetically activates NAMPT to promote tumor progression and metastasis. Furthermore, these data identify NAMPT-AS/NAMPT as promising therapeutic targets in patients with TNBC. SIGNIFICANCE: Upregulation of the long noncoding antisense RNA of NAMPT gene (NAMPT-AS) is associated with metastasis and poor prognosis in TNBC. 

Retracted: No

PubPeer comments:
 2021 correction. https: cancerres.aacrjournals.org content 81 11 3145#ref-1 In the original version of this article (1), the authors inadvertently incorporated the incorrect image in the sh8 migration panel in Fig. 5C. Likewise, incorrect images were included in Supplementary Fig. S8C for the MDA-MB-231 invasion and MDA-MB-468 migration panels in the pcDNA3.1+NC and pcDNA3.1+miR-548b-3p mimics subgroups. The correct images have been provided, and the error has been corrected in the latest online HTML and PDF versions of the article. The authors regret this error. Reference 1.u21b5Zhang H, Zhang N, Liu Y, Su P, Liang Y, Li Y, et al. Epigenetic regulation of NAMPT by NAMPT-AS drives metastatic progression in triple-negative breast cancer. Cancer Res 2019;79:3347u201359. ,