共查询到20条相似文献,搜索用时 31 毫秒
1.
Gastric cancer (GC) is the fifth most common tumor and the third most deadly cancer worldwide. N6-methyladenosine (m 6A) modification has been reported to play a regulatory role in human cancers. However, the exact role of m 6A in GC remains largely unknown, and the dysregulation of m 6A on mitochondrial metabolism has never been studied. In the present study, we demonstrated that FTO, a key demethylase for RNA m 6A modification, was up-regulated in GC tissues, especially in tissues with liver metastasis. Functionally, FTO acted as a promoter for the proliferation and metastasis in GC. Moreover, FTO enhanced the degradation of caveolin-1 mRNA via its demethylation, which regulated the mitochondrial fission/fusion and metabolism. Collectively, our current findings provided some valuable insights into FTO-mediated m 6A demethylation modification and could be used as a new strategy for more careful surveillance and aggressive therapeutic intervention.Subject terms: Cancer genomics, Gastrointestinal diseases 相似文献
2.
As the first identified N 6-methyladenosine (m 6A) demethylase, fat mass and obesity-associated (FTO) protein is associated with fatty acid synthase (FASN) and lipid accumulation. However, little is known about the regulatory role of FTO in the expression of FASN and de novo lipogenesis through m 6A modification. In this study, we used FTO small interfering RNA to explore the effects of FTO knockdown on hepatic lipogenesis and its underlying epigenetic mechanism in HepG2 cells. We found that knockdown of FTO increased m 6A levels in total RNA and enhanced the expression of YTH domain family member 2 which serves as the m 6A-binding protein. The de novo lipogenic enzymes and intracellular lipid content were significantly decreased under FTO knockdown. Mechanistically, knockdown of FTO dramatically enhanced m 6A levels in FASN messenger RNA (mRNA), leading to the reduced expression of FASN mRNA through m 6A-mediated mRNA decay. The protein expressions of FASN along with acetyl CoA carboxylase and ATP-citrate lyase were further decreased, which inhibited de novo lipogenesis, thereby resulting in the deficiency of lipid accumulation in HepG2 cells and the induction of cellular apoptosis. The results reveal that FTO regulates hepatic lipogenesis via FTO-dependent m 6A demethylation in FASN mRNA and indicate the critical role of FTO-mediated lipid metabolism in the survival of HepG2 cells. This study provides novel insights into a unique RNA epigenetic mechanism by which FTO mediates hepatic lipid accumulation through m 6A modification and indicates that FTO could be a potential target for obesity-related diseases and cancer. 相似文献
5.
Heart failure (HF) is the end stage of many cardiovascular diseases and seriously threatens people’s health. This article aimed to explore the biological role of fat-mass and obesity-associated gene (FTO) in HF. We constructed HF mouse model by transverse aortic constriction or intraperitoneal injection of doxorubicin. Mouse myocardial cells were exposed to hypoxia/reoxygenation (H/R). FTO and Mhrt were downregulated in heart tissues of HF mice. HF mice exhibited an increase in the total levels of N6 methyladenosine (m6A) and the m6A levels of Mhrt. Moreover, FTO overexpression caused an upregulation of Mhrt and reduced m6A modification of Mhrt in the H/R-treated myocardial cells. FTO upregulation repressed apoptosis of H/R-treated myocardial cells. FTO knockdown had the opposite results. Mhrt overexpression reduced apoptosis of H/R-treated myocardial cells. Moreover, the influence conferred by FTO upregulation was abolished by Mhrt knockdown. In conclusion, our data demonstrate that FTO overexpression inhibits apoptosis of hypoxia/reoxygenation-treated myocardial cells by regulating m6A modification of Mhrt. Thus, FTO may be a target gene for HF treatment. 相似文献
6.
N 6-methyladenosine (m 6A) is the most prevalent internal mRNA modification in eukaryotes. Loss of m 6A demethylase FTO increases m 6A levels and inhibits adipogenesis of preadipocytes. However, its underlying mechanism remains elusive. Here, we demonstrated that silencing FTO inhibited adipogenesis of preadipocytes through impairing cell cycle progression at the early stage of adipogenesis. FTO knockdown markedly decreased the expression of CCNA2 and CDK2, crucial cell cycle regulators, leading to delayed entry of MDI-induced cells into G2 phase. Furthermore, the m 6A levels of CCNA2 and CDK2 mRNA were significantly upregulated following FTO knockdown. m 6A-binding protein YTHDF2 recognized and decayed methylated mRNAs of CCNA2 and CDK2, leading to decreased protein expression, thereby prolonging cell cycle progression and suppressing adipogenesis. Our work unravels that FTO regulates adipogenesis by controlling cell cycle progression in an m 6A-YTHDF2 dependent manner, which provides insights into critical roles of m 6A methylation in adipogenesis. 相似文献
8.
Two human demethylases, the fat mass and obesity-associated (FTO) enzyme and ALKBH5, oxidatively demethylate abundant N6-methyladenosine (m 6A) residues in mRNA. Achieving a method for selective inhibition of FTO over ALKBH5 remains a challenge, however. Here, we have identified meclofenamic acid (MA) as a highly selective inhibitor of FTO. MA is a non-steroidal, anti-inflammatory drug that mechanistic studies indicate competes with FTO binding for the m 6A-containing nucleic acid. The structure of FTO/MA has revealed much about the inhibitory function of FTO. Our newfound understanding, revealed herein, of the part of the nucleotide recognition lid (NRL) in FTO, for example, has helped elucidate the principles behind the selectivity of FTO over ALKBH5. Treatment of HeLa cells with the ethyl ester form of MA (MA2) has led to elevated levels of m 6A modification in mRNA. Our collective results highlight the development of functional probes of the FTO enzyme that will (i) enable future biological studies and (ii) pave the way for the rational design of potent and specific inhibitors of FTO for use in medicine. 相似文献
11.
ObjectivesWe aimed at probing impact of LINC00858 on esophageal squamous cell carcinoma (ESCC) progression via ZNF184-FTO-m 6A-MYC axis. MethodsExpression of related genes (LINC00858, ZNF184, FTO, and MYC) was detected in ESCC tissues or cells and their relationships were assessed. After expression alterations in ESCC cells, cell proliferation, invasion, migration, and apoptosis were detected. Tumor formation in nude mice was conducted. ResultsLINC00858, ZNF184, FTO, and MYC were overexpressed in ESCC tissues and cells. LINC00858 enhanced ZNF184 expression to upregulate FTO, which augmented MYC expression. LINC00858 knockdown diminished ESCC cell proliferative, migratory, and invasive properties while elevating apoptosis, which was negated by FTO overexpression. FTO knockdown exerted similar functions of LINC00858 knockdown on ESCC cell movements, which was annulled by MYC upregulation. Silencing LINC00858 repressed tumor growth and related gene expression in nude mice. ConclusionsLINC00858 modulated MYC m 6A modification via FTO by recruiting ZNF184, thus facilitating ESCC progression. 相似文献
13.
Fat mass and obesity-associated (FTO) protein, the first m 6A demethylase identified in 2011, regulates multiple aspects of RNA biology including splicing, localization, stability, and translation. Accumulating data show that FTO is involved in numerous physiological processes and is implicated in multiple cancers including renal cell carcinoma (RCC). However, the exact role of FTO in RCC remains controversial. Some studies demonstrated that decreased FTO expression was associated with aggressive clinical features and shorter overall survival in clear cell RCC (ccRCC) patients, while others found that FTO inhibition selectively reduced the growth and survival of VHL-deficient ccRCC cells in vitro and in vivo. Here, we review the evidence supporting either a promoting or suppressive role of FTO in kidney cancers, the mechanisms of action of FTO, and recent progress in developing FTO inhibitors. 相似文献
17.
Our previous works revealed that human ribosomal protein S13 (RPS13) was up‐regulated in multidrug‐resistant gastric cancer cells and overexpression of RPS13 could protect gastric cancer cells from drug‐induced apoptosis. The present study was designed to explore the role of RPS13 in tumorigenesis and development of gastric cancer. The expression of RPS13 in gastric cancer tissues and normal gastric mucosa was evaluated by immunohistochemical staining and Western blot analysis. It was found RPS13 was expressed at a higher level in gastric cancer tissues than that in normal gastric mucosa. RPS13 was then genetically overexpressed in gastric cancer cells or knocked down by RNA interference. It was demonstrated that up‐regulation of RPS13 accelerated the growth, enhanced in vitro colony forming and soft agar cologenic ability and promoted in vivo tumour formation potential of gastric cancer cells. Meanwhile, down‐regulation of RPS13 in gastric cancer cells resulted in complete opposite effects. Moreover, overexpression of RPS13 could promote G1 to S phase transition whereas knocking down of RPS13 led to G1 arrest of gastric cancer cells. It was further demonstrated that RPS13 down‐regulated p27 kip1 expression and CDK2 kinase activity but did not change the expression of cyclin D, cyclin E, CDK2, CDK4 and p16 INK4A. Taken together, these data indicate that RPS13 could promote the growth and cell cycle progression of gastric cancer cells at least through inhibiting p27 kip1 expression. 相似文献
18.
Diffuse-type solid tumors are often composed of a high proportion of rarely proliferating (i.e., dormant) cancer cells, strongly indicating the involvement of cancer stem cells (CSCs) Although diffuse-type gastric cancer (GC) patients have a poor prognosis due to high-frequent development of peritoneal dissemination (PD), it is limited knowledge that the PD-associated CSCs and efficacy of CSC-targeting therapy in diffuse-type GC. In this study, we established highly metastatic GC cell lines by in vivo selection designed for the enrichment of PD-associated GC cells. By microarray analysis, we found C-X-C chemokine receptor type 4 (CXCR4) can be a novel marker for highly metastatic CSCs, since CXCR4-positive cells can grow anchorage-independently, initiate tumors in mice, be resistant to cytotoxic drug, and produce differentiated daughter cells. In clinical samples, these CXCR4-positive cells were found from not only late metastasis stage (accumulated ascites) but also earlier stage (peritoneal washings). Moreover, treatment with transforming growth factor-β enhanced the anti-cancer effect of docetaxel via induction of cell differentiation/asymmetric cell division of the CXCR4-positive gastric CSCs even in a dormant state. Therefore, differentiation inducers hold promise for obtaining the maximum therapeutic outcome from currently available anti-cancer drugs through re-cycling of CSCs. 相似文献
20.
ObjectiveIn human prostate cancer cells, a selective Epac agonist, 8-CPT-2Me-cAMP, upregulates cell proliferation and survival via activation of Ras-MAPK and PI- 3-kinase-Akt-mTOR signaling cascades. Here we examine the role of inflammatory mediators in Epac1-induced cellular proliferation by determining the expression of the pro-inflammatory markers p-cPLA2, COX-2, and PGE 2 in prostate cancer cells treated with 8-CPT-2Me-cAMP. MethodsWe employed inhibitors of COX-2, mTORC1, and mTORC2 to probe cyclic AMP-dependent pathways in human prostate cancer cells. RNAi targeting Epac1, Raptor, and Rictor was also employed in these studies. Results8-CPT-2Me-cAMP treatment caused a 2–2.5-fold increase of p-cPLA2 S505, COX-2, and PGE 2 levels in human prostate cancer cell lines. Pretreatment of cells with the COX-2 inhibitor SC-58125 or the EP4 antagonist AH-23848, or with an inhibitor of mTORC1 and mTORC2, Torin1, significantly reduced the Epac1-dependent increase of p-cPLA2 and COX-2, p-S6-kinase T389, and p-AKT S473. In addition, Epac1-induced protein and DNA synthesis were greatly reduced upon pretreatment of cells with either COX-2, EP4, or mTOR inhibitors. Transfection of prostate cancer cells with Epac1 dsRNA, Raptor dsRNA, or Rictor dsRNA profoundly reduced Epac1-dependent increases in p-cPLA2 and COX-2. ConclusionWe show that Epac1, a downstream effector of cAMP, functions as a pro-inflammatory modulator in prostate cancer cells and promotes cell proliferation and survival by upregulating Ras-MAPK, and PI 3-kinase-Akt-mTOR signaling. 相似文献
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