FTO suppresses glycolysis and growth of papillary thyroid cancer via decreasing stability of APOE mRNA in an N6-methyladenosine-dependent manner

Abstract

Background N6-methyladenosine (m6A) modification is the most common chemical modification in mammalian mRNAs, and it plays important roles by regulating several cellular processes. Previous studies report that m6A is implicated in modulating tumorigenesis and progression. However, dysregulation of m6A modification and effect of m6A demethylase fat-mass and obesity-associated protein (FTO) on glucose metabolism has not been fully elucidated in papillary thyroid cancer (PTC). Methods Quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry were performed to explore the expression profile of FTO in PTC tissues and adjacent non-cancerous thyroid tissues. Effects of FTO on PTC glycolysis and growth were investigated through in vitro and in vivo experiments. Mechanism of FTO-mediated m6A modification was explored through transcriptome-sequencing (RNA-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), MeRIP-qPCR, luciferase reporter assays, RNA stability assay and RNA immunoprecipitation assay. Results FTO expression was significantly downregulated in PTC tissues. Functional analysis showed that FTO inhibited PTC glycolysis and growth. Further analyses were conducted to explore FTO-mediated m6A modification profile in PTC cells and Apolipoprotein E (APOE) was identified as the target gene for FTO-mediated m6A modification using RNA-seq and MeRIP-seq. FTO knockdown significantly increased APOE mRNA m6A modification and upregulated its expression. FTO-mediated m6A modification of APOE mRNA was recognized and stabilized by the m6A reader IGF2BP2. The findings showed that APOE also promoted tumor growth through glycolysis in PTC. Analysis showed that FTO/APOE axis inhibits PTC glycolysis by modulating IL-6/JAK2/STAT3 signaling pathway. Conclusion FTO acts as a tumor suppressor to inhibit tumor glycolysis in PTC. The findings of the current study showed that FTO inhibited expression of APOE through IGF2BP2-mediated m6A modification and may inhibit glycolytic metabolism in PTC by modulating IL-6/JAK2/STAT3 signaling pathway, thus abrogating tumor growth.

Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

“…However, m 6 A methylation modifiers act as a double-edged sword in the regulation of cellular processes associated with glycolysis, which may depend on the large number of RNA-binding proteins (RBPs), including both m 6 A methylation reading and non-reading proteins, and their recognition sites. Huang et al [ 66 ] suggested that FTO suppresses APOE through IGF2BP2-mediated m 6 A methylation and inhibits glycolytic metabolism in PTC through regulating the IL-6/JAK2/STAT3 signaling pathway, thereby retarding thyroid cancer cell growth. Correspondingly, YTHDC1-mediated enhancement of miR-30d suppressed pancreatic tumorigenesis via attenuation of RUNX1-induced transcriptional activation of the Warburg effect [ 67 ].…”

The role of Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) as m6A readers in cancer

“…In similar with c-MYC, oncogene SOX2 is highly susceptible to m 6 A modification 165 , 166 . In thyroid cancer, m 6 A demethylase FTO inhibits cell growth and glycolysis by reducing the mRNA stability of target, APOE in IGF2BP2-mediated m 6 A-dependent manner 167 . IGF2BP2 also promotes lymphatic metastasis and epithelial-mesenchymal transition (EMT) of head and neck squamous carcinoma cells by stabilizing slug mRNA in an m 6 A-dependent manner 168 .…”

Methyladenosine Modification in RNAs: From Regulatory Roles to Therapeutic Implications in Cancer

“…FTO suppresses the oncogenesis of pancreatic cancer by inhibiting Wnt signaling as well as demethylating PJA2 [68]. In papillary thyroid cancer (PTC), Huang et al, found that FTO restrains the stability of Apolipoprotein E (APOE), repressing the glycolysis and growth of PTC in an m 6 A-IGF2BP2-mediated manner [69]. Another type of demethylase, ALKBH5, was found to promote oncogenesis of AML selectively in an m 6 A-dependent manner [70].…”

“…METTL3 was found to upregulate glycolysis in CRC by stabilizing HK2 and SLC2A1 in an m 6 A-IGF2BP2/3-dependent manner, leading to cancer progression [41]. Conversely, FTO represses the glycolysis of PTC by destabilizing APOE, thus restraining the growth of cancer [69]. By modulating hypoxia and glycolysis in the TME, altering m 6 A modifications may serve as a therapeutic strategy in treating cancers, though more in-depth research is required.…”