Abstract
BackgroundCircular RNAs (circRNAs) play important roles in cancer progression and metabolism regulation. Serine/glycine metabolism supports the growth of cancer cells by contributing to their anabolic demands and epigenome as well as by regulating their redox state. However, the role of circRNA in the regulation of serine/glycine metabolism has not been well elucidated.MethodsMicroarray analysis was used to screen differentially expressed novel circRNAs. qRT-PCR and FISH were utilized to analyzed the expression of circMYH9. CCK8, colony formation and FACS were used to analyze proliferation of colorectal cancer (CRC) cells. Xenograft experiments were used to analyze tumor growth in vivo. RNA-sequencing, immunoblot and LC–MS were used to identify the downstream metabolic pathway of circMYH9. ChIRP, Mass Spectrometry, RIP and RNA pulldown were utilized to test the interaction between circMYH9, hnRNPA2B1 and p53 pre-mRNA. ChIP-qPCR was used to analyze the binding sites of HIF-1α. Chemically-induced CRC mice were generated to evaluate the role of circMYH9 in tumorigenesis.ResultsWe identified an intron-derived circRNA, circMYH9, which was significantly upregulated in CRC tissues. A higher circMYH9 level correlated with shorter relapse-free survival and overall survival of CRC patients. CircMYH9 promoted serine/glycine metabolism, the NAD + /NADH ratio, and glutathione recycling and inhibited reactive oxygen species (ROS) in a p53-dependent manner, impacting tumour growth. Mechanistically, circMYH9 destabilized the pre-mRNA of p53 by recruiting hnRNPA2B1 in the nucleus. hnRNPA2B1 bound to N6-methyladenosine sites on the 3' untranslated region of p53 pre-mRNA and maintained its stability. Moreover, a lack of amino acids led to an elevated level of ROS, resulting in increased HIF1α, which promoted circMYH9 expression by binding to the promoter region. Furthermore, in vivo AAV9-mediated transfection of circMYH9 could drive chemically-induced carcinogenesis by suppressing p53 in mice.ConclusionsThe overexpression of circMYH9 promotes CRC proliferation though modulating serine/glycine metabolism and redox homeostasis in a p53-dependent manner, and targeting circMYH9 and its pathway may be an effective strategy for the treatment of CRC.
Highlights
Metabolic reprogramming is an important characteristic of tumour cells [1]
Results circMYH9 was identified in colorectal cancer (CRC) tissues and cells To identify potential differentially expressed circRNAs, we screened circRNAs that may be differentially expressed in 10 paired CRC tissues and adjacent tissues from the GEO database (GSE126095)
RT-PCR and Quantitative real-time PCR (qRT-PCR) analysis indicated that circMYH9 could be amplified by divergent primers in cDNA, and no other products were observed in the genomic DNA groups (Fig. 1E)
Summary
Metabolic reprogramming is an important characteristic of tumour cells [1]. Serine and glycine (SG) metabolism, as an important branch of amino acid metabolism, can support cell proliferation [3]. Cells can obtain serine by either import from the extracellular environment or intracellular synthesis from glucose, while the increased demand for serine in tumour cells leads to the reprogramming of serine metabolism [4]. Dysregulated serine metabolism in cancer provides carbons for nucleotide synthesis, increases antioxidant capacity to maintain redox balance, and maintains the stability of the tumour microenvironment [5,6,7,8]. Serine/ glycine metabolism supports the growth of cancer cells by contributing to their anabolic demands and epigenome as well as by regulating their redox state. The role of circRNA in the regulation of serine/glycine metabolism has not been well elucidated
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