Epigenetic Regulation of NAMPT by NAMPT-ASDrives Metastatic Progression in Triple-Negative Breast Cancer

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.

Impact of histotypes on preferential organ‐specific metastasis in triple‐negative breast cancer

“…Another research found that the genomic mutations were originated from the primary tumor and maintained through metastatic spreading, of which TP53 mutation was a recurrent founding mutation in primary and metastatic tumors . We also reported genes like NAMPT , SREBP1 , and MTDH could drive metastatic progression in TNBC . The alteration of genes cluster could not only influence malignant behaviors, but also transform pathomorphological features.…”

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

“…NAMPT overexpression in experimental models of glioblastoma resulted in a cellular phenotype consistent with that of a cancer stem-like cell (126), while pharmacological and genetic inhibition of NAMPT decreased the ability of glioblastoma stem cells to self-renew and form in vivo tumors (131). In one study, the loss of cancer stem cell pluripotency upon inhibition of NAMPT was the result of an excess of autophagy, a well-described consequence of NAMPT inhibition (15,58,64,121,(132)(133)(134)(135), which disrupted the maintenance of cancer cell stemness (136). NAMPT inhibition has also been shown to reverse the ability of cancer cells to dedifferentiate (137).…”

Systematic characterization of non‐coding RNAs in triple‐negative breast cancer

“…One was that the transcription of NAMPT was activated by NAMPT‐AS, thereby recruiting POU2F2. The other was that NAMPT‐AS acted as ceRNA to rescue NAMPT degradation from miR‐548b‐3p 10 . A previous report indicated that a novel miRNA sponge, lincRNA ROR, was dramatically upregulated in TNBC and interacted with miR‐145 to regulate cancer cell invasion by targeting ARF6 11 .…”