A long noncoding RNA connects c-Myc to tumor metabolism

Abstract

Long noncoding RNAs (lncRNAs) have been implicated in a variety of physiological and pathological processes, including cancer. In prostate cancer, prostate cancer gene expression marker 1 (PCGEM1) is an androgen-induced prostate-specific lncRNA whose overexpression is highly associated with prostate tumors. PCGEM1's tumorigenic potential has been recently shown to be in part due to its ability to activate androgen receptor (AR). Here, we report a novel function of PCGEM1 that provides growth advantages for cancer cells by regulating tumor metabolism via c-Myc activation. PCGEM1 promotes glucose uptake for aerobic glycolysis, coupling with the pentose phosphate shunt to facilitate biosynthesis of nucleotide and lipid, and generates NADPH for redox homeostasis. We show that PCGEM1 regulates metabolism at a transcriptional level that affects multiple metabolic pathways, including glucose and glutamine metabolism, the pentose phosphate pathway, nucleotide and fatty acid biosynthesis, and the tricarboxylic acid cycle. The PCGEM1-mediated gene regulation takes place in part through AR activation, but predominantly through c-Myc activation, regardless of hormone or AR status. Significantly, PCGEM1 binds directly to target promoters, physically interacts with c-Myc, promotes chromatin recruitment of c-Myc, and enhances its transactivation activity. We also identified a c-Myc binding domain on PCGEM1 that contributes to the PCGEM1-dependent c-Myc activation and target induction. Together, our data uncover PCGEM1 as a key transcriptional regulator of central metabolic pathways in prostate cancer cells. By being a coactivator for both c-Myc and AR, PCGEM1 reprograms the androgen network and the central metabolism in a tumor-specific way, making it a promising target for therapeutic intervention.L ong noncoding RNAs (lncRNAs) have recently drawn increasing attention as important players in physiological and pathological processes. In cancer, aberrant expression and mutations of lncRNAs can contribute to tumor development and progression by promoting proliferation, invasion, metastasis, and survival (1-3). LncRNAs thus may serve as diagnostic biomarkers and therapeutic targets for cancer. LncRNAs function at several levels of cellular processes, and the majority thus far studied are involved in gene regulation either at the transcriptional or posttranscriptional level (4). At the transcriptional level, lncRNA can serve as a chaperon or scaffold to deliver transcriptional factor to the chromatin site, to modulate the chromatin conformation by recruiting histone-modifying complexes, and to connect distal gene-regulatory elements together to effectively modulate the transcription of the targeted loci (4).Prostate cancer gene expression marker 1 (PCGEM1) is a prostate tissue-specific lncRNA highly associated with prostate cancer (5). Over 80% of patient specimens show elevated levels (5), and the occurrence of PCGEM1 overexpression seems to be significantly higher in African-American patients, whose population has the highest pr...

MINCR is a MYC-induced lncRNA able to modulate MYC’s transcriptional network in Burkitt lymphoma cells

“…In this model, we can imagine MINCR binding either directly to MYC or to a MYC binding partner and influencing the ability of the MYC transactivation complex to bind promoters and affect transcription. The lncRNA PCGEM1, for instance, has recently been shown to bind MYC directly and enhance its ability to regulate the transcription of metabolic genes (59). In support of this model, we have observed a decrease in MYC binding to the promoters of a set of the identified cell cycle genes on MINCR knockdown (Fig.…”

Overexpression of Long Non-Coding RNA ZXF2 Promotes Lung Adenocarcinoma Progression Through c-Myc Pathway

“…The potential molecular mechanisms underlying ZXF2 mediated regulation of c-myc could be summarized as following: First, given the fact that both human c-myc and ZXF2 are adjacently located on chromosome 8 (8q24.2), and some lncRNAs have been demonstrated to control myc expression through regulate long-range interactions between the MYC promoter and its enhancers in cancer cells [23,24], it is possible that ZXF2 functions as a transcriptional enhancer of MYC gene. Second, a recent elegant study show that lncRNA can directly bind and serve as a coactivator of c-Myc to activate transactivation functions of c-Myc [25]. Finally, lncRNA has been shown to regulate mRNA stability of c-Myc [26].…”

LNMICC Promotes Nodal Metastasis of Cervical Cancer by Reprogramming Fatty Acid Metabolism

“…Current evidence demonstrates that lncRNAs play both pro-and anti-metastatic roles via the regulation of EMT and angiogenesis as well as binding to certain metastatic factors [21]. In addition, lncRNAs, as key transcriptional regulators of central metabolic pathways, can provide proliferating advantages through significantly enhancing the biosynthesis of FA [22]. This strong evidence led us to speculate whether LNMICC promotes LN metastasis in cervical cancer through the FABP5-mediated reprogramming of FA metabolism.…”