Abstract
The nicotinate phosphoribosyltransferase (NAPRT) gene has gained relevance in the research of cancer therapeutic strategies due to its main role as a NAD biosynthetic enzyme. NAD metabolism is an attractive target for the development of anti-cancer therapies, given the high energy requirements of proliferating cancer cells and NAD-dependent signaling. A few studies have shown that NAPRT expression varies in different cancer types, making it imperative to assess NAPRT expression and functionality status prior to the application of therapeutic strategies targeting NAD. In addition, the recent finding of NAPRT extracellular form (eNAPRT) suggested the involvement of NAPRT in inflammation and signaling. However, the mechanisms regulating NAPRT gene expression have never been thoroughly addressed. In this study, we searched for NAPRT gene expression regulatory mechanisms in transcription factors (TFs), RNA binding proteins (RBPs) and microRNA (miRNAs) databases. We identified several potential regulators of NAPRT transcription activation, downregulation and alternative splicing and performed GO and expression analyses. The results of the functional analysis of TFs, RBPs and miRNAs suggest new, unexpected functions for the NAPRT gene in cell differentiation, development and neuronal biology.
Highlights
Nicotinate phosphoribosyltransferase (NAPRT) is an enzyme from NAD (Nicotinamide Adenine Dinucleotide) biosynthesis and is mostly studied as a cancer biomarker.One of the cancer therapeutic strategies targeting NAD metabolism is the use of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors [1,2,3,4]
In order to search for transcription factors (TFs) that could regulate NAPRT gene expression, we surveyed one database with experimental data from the Encyclopedia of DNA Elements (ENCODE) Project [19]—Factorbook [20]—and four sources of computational predictions of transcription factor binding sites (TFBS)—UniPROBE [21]—PROMO v3.0.2, which uses the TFBS defined in the TRANSFAC database v8.3 [22,23], MotifMap [24,25] and CTCFBS v2.0 [26], using NAPRT 5 UTR sequence as an input
In addition to the expected processes related to the transcription regulation and the involvement in the RNA metabolic process, Gene Ontology (GO) analysis of the 80 TFs revealed an overall overrepresentation for genes involved in signaling and response to stimulus (Supplementary Table S4), such as “response to UV-C” or “positive regulation of defense response to virus by host”
Summary
Nicotinate phosphoribosyltransferase (NAPRT) is an enzyme from NAD (Nicotinamide Adenine Dinucleotide) biosynthesis and is mostly studied as a cancer biomarker.One of the cancer therapeutic strategies targeting NAD metabolism is the use of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors [1,2,3,4]. NAMPT is the ratelimiting enzyme of the main NAD salvage pathway, which uses nicotinamide, while NAPRT is responsible for NAD production via the nicotinic acid precursor, known as the Preiss–Handler pathway [5,6]. In this context, NAPRT became an important biomarker for the use of nicotinic acid as a co-adjuvant in NAPRT-negative tumors [1] and for coinhibition in the cancer types that highly express NAPRT [7]. In order to select the types of cancer that would better respond to NAMPT inhibition, a determination should be made on whether NAPRT is expressed and functional
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