Abstract
BackgroundDysregulation of fatty acid (FA) metabolism is involved in hepatocellular carcinoma (HCC) development. Non-POU domain-containing octamer binding protein (NONO), known as the component of nuclear paraspeckles, has recently been found to promote HCC progression. In this study, we investigated the functions of NONO in regulating de novo FA synthesis and its underling mechanism during HCC development.MethodsThe roles of NONO in HCC development by applying gene function loss analysis in HCC cells were detected by quantitative real-time polymerase chain reaction, cell proliferation, and cell invasion assays. The underlying mechanism of NONO in HCC development was examined by western blotting, subcellular fractionation, RNA-binding protein immunoprecipitation-sequencing, chromatin immunoprecipitation, co-immunoprecipitation and mass spectrometry. The effect of NONO on tumorigenesis in vivo was performed with a subcutaneous xenograft mouse model of HCC.ResultsNONO promotes HCC progression by interacting with and increasing ATP-citrate lyase (ACLY) mRNA to enhance FA biosynthesis. Furthermore, NONO promotes ACLY expression through enhancing nuclear ACLY mRNA stability in Diethylnitrosamine-stimulated HCC cells, not related to nuclear paraspeckles. Moreover, we find that NONO/SFPQ (Splicing factor proline and glutamine rich) heterodimer is essential for NONO interacting with ACLY mRNA in DEN stimulated HCC cells. In addition, NONO, Insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) and ACLY expressions contribute HCC development in mice and are related to poor survival.ConclusionNONO promotes HCC progression by enhancing FA biosynthesis through interacting with ACLY mRNA and provide a novel potential target for HCC therapy.
Highlights
Dysregulation of fatty acid (FA) metabolism is involved in hepatocellular carcinoma (HCC) development
NONO promotes DEN‐induced HCC cell growth and invasion, and is associated with FA synthesis signaling To explore whether NONO is involved in HCC progression, we first detected the expression levels of NONO in HCC cells stimulated with Diethylnitrosamine (DEN), a commonly used drug to induced hepatocarcinogenesis in vivo [30]
Gene ontology (GO) analysis showed that the overlapped 222 genes identified in MHCC97H cells stimulated with DEN for 12 and 24 h were involved in carbon metabolism, fatty acid elongation, and AMPK (Adenosine Monophosphate-Activated Protein Kinase) signaling (Fig. 1g)
Summary
Dysregulation of fatty acid (FA) metabolism is involved in hepatocellular carcinoma (HCC) development. We investigated the functions of NONO in regulating de novo FA synthesis and its underling mechanism during HCC development. The well-known “Warburg phenomenon” is that cancer cells metabolize glucose into lactate under aerobic conditions, not utilizing the route of oxidative decarboxylation by the citric acid cycle for energy production [10]. Cancer cells use cytoplasmic acetyl-CoA as substrate for FA synthesis. More and more studies have identified that FA synthesis, such as ACLY, ACC, FASN and stearoyl-CoA-desaturase 1 (SCD1), are highly expressed in many cancers, including HCC [14,15,16,17]. The underlying mechanism in regulating de novo FA synthesis during HCC development is still not clearly understood [18]
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