LncRNA NBR2 engages a metabolic checkpoint by regulating AMPK under energy stress

Abstract

Long noncoding RNAs (lncRNAs) have emerged as critical regulators in various cellular processes. However, the potential involvement of lncRNAs in kinase signaling remains largely unknown. AMP-activated protein kinase (AMPK) acts as a critical sensor of cellular energy status. Here we show that lncRNA NBR2 (neighbor of BRCA1 gene 2) is induced by the LKB1-AMPK pathway under energy stress. Upon energy stress, NBR2 in turn interacts with AMPK and promotes AMPK kinase activity, thus forming a feed-forward loop to potentiate AMPK activation during energy stress. Depletion of NBR2 attenuates energy stress-induced AMPK activation, resulting in unchecked cell cycling, altered apoptosis/autophagy response, and increased tumor development in vivo. NBR2 is down-regulated and its low expression correlates with poor clinical outcomes in some human cancers. Together, our study uncovers a mechanism coupling lncRNAs with metabolic stress response, and provides a broad framework to further understand the regulation of kinase signaling by lncRNAs.

NBR2: A former junk gene emerges as a key player in tumor suppression

“…Since many lncRNAs function to regulate the transcription of neighboring genes, the hypothesis that NBR2 regulates BRCA1 transcription is of particular interest. Although our current data do not support such a hypothesis, 8 another study showed that NBR2 knockdown modestly downregulated BRCA1 mRNA level. 10 Since these studies were conducted in different cell lines with different knockdown efficiencies, it is possible that NBR2 regulation of BRCA1 expression is context dependent, and it will be important to further clarify this question in future studies.…”

“…Whether the NBR2-AMPK regulation discovered in our study can be applied to other lncRNAs that may regulate kinase function also awaits further investigation. In addition, our data show that NBR2 overexpression still partially inhibited tumor cell proliferation in AMPK-deficient cells, 8 suggesting the existence of AMPK-dependent and -independent mechanisms that mediate NBR2 function in tumor suppression. Since many lncRNAs function to regulate the transcription of neighboring genes, the hypothesis that NBR2 regulates BRCA1 transcription is of particular interest.…”

“…Further functional studies showed that NBR2 exerted its tumor suppressive function at least in part through regulation of AMPK activity. 8 Taken together, our results not only reveal the biological function of NBR2 in tumor suppression but also provide a new conceptual framework to understand the regulation of kinase signaling by lncRNAs. Several important questions remain to be addressed in future studies.…”

“…8 The discovery stemmed from our analysis and characterization of energy stress-induced lncRNAs. RNA sequencing and computational analyses of non-coding RNA profiles of cells cultured in glucose-containing or glucose-free medium identified NBR2 as one of several lncRNAs that were induced upon glucose starvation.…”

Systemic analysis of lncRNA and miRNA expression profiles with associated ceRNA network in glioblastoma

“…Additionally, lncRNAs can regulate kinase functions. LncRNA NBR2 engages a metabolic checkpoint by regulating AMP-www.impactjournals.com/oncotarget activated protein kinase (AMPK) under energy stress [10]. Accumulating evidence suggests that lncRNAs play a role in fundamental biological functions, and dysregulation of lncRNAs contributes to cancer development, progression, and metastasis in many malignancies [11].…”