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M6A demethylase FTO induces NELL2 expression by inhibiting E2F1 m6A modification leading to metastasis of non-small cell lung cancer.

ABSTRACT: Non-small cell lung cancer (NSCLC) represents one of the primary causes of cancer-related mortality all over the world. Following our initial finding of the upregulated expression of E2F transcription factor-1 (E2F1) in the NSCLC-related microarray, this study aimed to explore the regulatory role of E2F1 and underlying mechanism in NSCLC development. NSCLC cell viability, migration, and invasion were evaluated utilizing Cell Counting Kit 8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), wound-healing, and Transwell assays. Loss- and gain-function assays were performed to determine the effects of the fat mass and obesity-associated protein (FTO)/E2F1/neural epidermal growth factor-like 2 (NELL2) axis on NSCLC cell behaviors in vitro and NSCLC tumor growth in vivo. E2F1 was highly expressed in both NSCLC tissues and cells. E2F1 augmented the viability, migration, and invasion of NSCLC cells, which was attributable to E2F1 transcriptionally activating NELL2. FTO upregulated the expression of E2F1 by inhibiting the m6A modification of E2F1. The FTO/E2F1/NELL2 axis modulated NSCLC cell viability, migration, and invasion in vitro as well as affected NSCLC tumor growth and metastasis in vivo. The FTO/E2F1/NELL2 axis may impart pro-tumorigenic effects on the cell behavior of NSCLC cells and thus accelerate NSCLC progression.

SUBMITTER: Wang Y

PROVIDER: S-EPMC8190133 | biostudies-literature |

REPOSITORIES: biostudies-literature

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m6A demethylase FTO suppresses pancreatic cancer tumorigenesis by demethylating <i>PJA2</i> and inhibiting Wnt signaling.

Project description:Pancreatic cancer is the deadliest malignancy of the digestive system and is the seventh most common cause of cancer-related deaths worldwide. The incidence and mortality of pancreatic cancer continue to increase, and its 5-year survival rate remains the lowest among all cancers. N6-methyladenine (m6A) is the most abundant reversible RNA modification in various eukaryotic messenger and long noncoding RNAs and plays crucial roles in the occurrence and development of cancers. However, the role of m6A in pancreatic cancer remains unclear. The present study aimed to explore the role of m6A and its regulators in pancreatic cancer and assess its underlying molecular mechanism associated with pancreatic cancer cell proliferation, invasion, and metastasis. Reduced expression of the m6A demethylase, fat mass and obesity-associated protein (FTO), was responsible for the high levels of m6A RNA modification in pancreatic cancer. Moreover, FTO demethylated the m6A modification of praja ring finger ubiquitin ligase 2 (PJA2), thereby reducing its mRNA decay, suppressing Wnt signaling, and ultimately restraining the proliferation, invasion, and metastasis of pancreatic cancer cells. Altogether, this study describes new, potential molecular therapeutic targets for pancreatic cancer that could pave the way to improve patient outcome.

| S-EPMC8385122 | biostudies-literature

m6A demethylase FTO promotes hepatocellular carcinoma tumorigenesis via mediating PKM2 demethylation.

Project description:N6-methyladenosine (m6A) acts as the most common mRNA modification in mammal cells. Fat Mass and Obesity-associated protein (FTO) is the firstly identified demethylase in the m6A modification. This research tries to discover the potential roles of FTO in the m6A modification in the hepatocellular carcinoma (HCC). FTO level was found to be up-regulated in the HCC tissue and cells. The over-expression of FTO was correlated to the poor prognosis of HCC individuals. Knockdown of FTO suppressed the proliferation and in vivo tumor growth, and induced the G0/G1 phase arrest. Mechanically, FTO triggered the demethylation of PKM2 mRNA and accelerated the translated production. Overall, this finding suggests the critical function of FTO in the HCC oncogenesis and its m6A modification.

| S-EPMC6789218 | biostudies-literature

N<sup>6</sup>-Methyladenosine RNA Demethylase FTO Promotes Gastric Cancer Metastasis by Down-Regulating the m6A Methylation of ITGB1.

Project description:Abnormal RNA m6A methylation is known to lead to the occurrence and progression of multiple cancers including gastric cancer (GC). However, the integrative effects of all m6A methylation regulators on GC prognosis are unclear. Our research aimed to globally analyze the prognosis values of all 33 m6A RNA methylation regulators in GC by univariate and multivariate Cox regression analyses. Among all 33 m6A RNA methylation regulators, fat mass and obesity-associated protein (FTO), an m6A demethylase, was identified as a key prognostic risk factor on overall survival (OS) of GC patients. It was found that FTO could promote GC cell migration and invasion abilities, and we predicted that ITGB1 was a demethylated target of FTO. Knockdown (KD) of FTO significantly down-regulated ITGB1 expression at both mRNA and protein levels and augmented ITGB1 mRNA m6A modification level. Moreover, overexpression (OE) of ITGB1 could partially reverse FTO-KD-inhibited migration and invasion of GC cells. Our study found that FTO was an independent risk factor for overall survival (OS) of GC patients and FTO could promote GC metastasis by upregulating the expression of Integrin β1(ITGB1) via decreasing its m6A level. These results indicated that FTO can be a potent GC biomarker for prognosis prediction as well as a potential target in GC treatment.

| S-EPMC8282183 | biostudies-literature

The m6A mRNA demethylase FTO in granulosa cells retards FOS-dependent ovarian aging.

Project description:Multifunctional N6-methyladenosine (m6A) has been revealed to be an important epigenetic component in various physiological and pathological processes, but its role in female ovarian aging remains unclear. Thus, we demonstrated m6A demethylase FTO downregulation and the ensuing increased m6A in granulosa cells (GCs) of human aged ovaries, while FTO-knockdown GCs showed faster aging-related phenotypes mediated. Using the m6A-RNA-sequence technique (m6A-seq), increased m6A was found in the FOS-mRNA-3'UTR, which is suggested to be an erasing target of FTO that slows the degradation of FOS-mRNA to upregulate FOS expression in GCs, eventually resulting in GC-mediated ovarian aging. FTO acts as a senescence-retarding protein via m6A, and FOS knockdown significantly alleviates the aging of FTO-knockdown GCs. Altogether, the abovementioned results indicate that FTO in GCs retards FOS-dependent ovarian aging, which is a potential diagnostic and therapeutic target against ovarian aging and age-related reproductive diseases.

| S-EPMC8316443 | biostudies-literature

The E2F1 oncogene transcriptionally regulates NELL2 in cancer cells.

Project description:NELL2 was first identified as a mammalian homolog of the chicken NEL protein. It was expressed in neurons and has been suggested to play a role in cell survival. However, no clear evidence has yet been available for functions of NELL2. In this study, we found two E2F1 binding sites located in the NELL2 promoter region. We examined the expression of NELL2 and E2F1 in human breast cancer cells (MDA-MB231, MCF7) and bladder cancer cells (5637, UC5). In MDA-MB231 and 5637, the expression levels of NELL2 and E2F1 were higher. To examine the interaction between E2F1 and NELL2, the binding activity was checked by a promoter assay and chromatin immunoprecipitation. From the results, we suggest that NELL2 is a novel target gene of E2F1, which is a key regulator of cell proliferation. We reveal that expression of NELL2 is regulated by E2F1, specifically, mRNA and protein levels of NELL2 are elevated upon activation of exogenous E2F1. Moreover, cells overexpressing NELL2 increased their invasive ability and an enhancement of the effect was observed when NELL2 and E2F1 were coexpressed in MDA-MB231 cells. Therefore, we suggest a novel activity for NELL2 in cancer progression through the regulation of E2F1.

| S-EPMC3752515 | biostudies-literature

The tRNA-Derived Fragment-3017A Promotes Metastasis by Inhibiting NELL2 in Human Gastric Cancer.

Project description:tRNA-derived fragments (tRFs) are a new classification of small non-coding RNAs (sncRNAs) derived from the specific cleavage of precursors and mature tRNAs. Accumulating recent evidence has shown that tRFs are frequently abnormal in several cancers. Nevertheless, the role of tRFs in gastric cancer and its mechanism remain unclear. In this study, we found abnormal expression of tRF-3017A (derived from tRNA-Val-TAC) in gastric cancer tissues and cell lines and confirmed its effect on promoting the invasion and migration of gastric cancer cells through functional experiments in vitro. Analysis of clinicopathologic data showed patients with higher tRF-3017A were associated with significantly higher lymph node metastasis. Mechanistic investigation implies that tRF-3017A regulates the tumor suppressor gene NELL2 through forming the RNA-induced silencing complex (RISC) with Argonaute (AGO) proteins. In this study, we found that higher tRF-3017A were associated with significantly higher lymph node metastasis in gastric cancer patients and the tRF-3017A may play a role in promoting the migration and invasion of gastric cancer cells by silencing tumor suppressor NELL2.

| S-EPMC7921707 | biostudies-literature

FTO: linking m6A demethylation to adipogenesis.

Project description:Polymorphism of the FTO gene encoding an N(6)-methyladenosine (m(6)A) RNA demethylase was robustly associated with human obesity; however, the mechanism by which FTO affects metabolism, considering its emerging role in RNA modification, is still poorly understood. A new study published in Cell Research reports novel functions implicating FTO in the regulation of mRNA alternative splicing in the control of adipogenesis.

| S-EPMC4650590 | biostudies-other

RNA N6-methyladenosine demethylase FTO promotes breast tumor progression through inhibiting BNIP3.

Project description:BackgroundN6-methyladenosine (m6A) modification is the most pervasive modification in mRNA, and has been considered as a new layer of epigenetic regulation on mRNA processing, stability and translation. Despite its functional significance in various physiological processes, the role of the m6A modification involved in breast cancer is yet fully understood.MethodsWe used the m6A-RNA immunoprecipitation sequencing to identify the potential targets in breast cancer. To determine the underlying mechanism for the axis of FTO-BNIP3, we performed a series of in vitro and in vivo assays in 3 breast cancer cell lines and 36 primary breast tumor tissues and 12 adjunct tissues.ResultsWe showed that FTO, a key m6A demethylase, was up-regulated in human breast cancer. High level of FTO was significantly associated with lower survival rates in patients with breast cancer. FTO promoted breast cancer cell proliferation, colony formation and metastasis in vitro and in vivo. We identified BNIP3, a pro-apoptosis gene, as a downstream target of FTO-mediated m6A modification. Epigenetically, FTO mediated m6A demethylation in the 3'UTR of BNIP3 mRNA and induced its degradation via an YTHDF2 independent mechanism. BNIP3 acts as a tumor suppressor and is negatively correlated with FTO expression in clinical breast cancer patients. BNIP3 dramatically alleviated FTO-dependent tumor growth retardation and metastasis.ConclusionsOur findings demonstrate the functional significance of the m6A modification in breast cancer, and suggest that FTO may serve as a novel potential therapeutic target for breast cancer.

| S-EPMC6437932 | biostudies-literature

RNA m6A demethylase FTO-mediated epigenetic up-regulation of LINC00022 promotes tumorigenesis in esophageal squamous cell carcinoma.

Project description:BackgroundLong non-coding RNA (LncRNA) controls cell proliferation and plays a significant role in the initiation and progression of esophageal squamous cell carcinoma (ESCC). N6-methyladenosine (m6A) modification now is recognized as a master driver of RNA function to maintain homeostasis in cancer cells. However, how m6A regulates LncRNA function and its role in tumorigenesis of ESCC remain unclear.MethodsMultiple ESCC datasets were used to analyze gene expression in tumor tissues and normal tissues. Kaplan-Meier method and the ROC curve were conducted to evaluate the prognostic value and diagnostic value of LINC00022 in ESCC, respectively. Both gain-of-function and loss-of-function experiments were employed to investigate the effects of LINC00022 on ESCC growth in vitro and in vivo. Bioinformatics analysis, colorimetric m6A assay, RIP, MeRIP and co-IP was performed to explore the epigenetic mechanism of LINC00022 up-regulation in ESCC.ResultsHere we report that m6A demethylation of LncRNA LINC00022 by fat mass and obesity-associated protein (FTO) promotes tumor growth of ESCC in vivo. Clinically, we revealed that LINC00022 was up-regulated in primary ESCC samples and was predictive of poor clinical outcome for ESCC patients. Mechanistically, LINC00022 directly binds to p21 protein and promotes its ubiquitination-mediated degradation, thereby facilitating cell-cycle progression and proliferation. Further, the elevated FTO in ESCC decreased m6A methylation of LINC00022 transcript, leading to the inhibition of LINC00022 decay via the m6A reader YTHDF2. Over-expression of FTO was shown to drive LINC00022-dependent cell proliferation and tumor growth of ESCC.ConclusionsThus, this study demonstrated m6A-mediated epigenetic modification of LncRNA contributes to the tumorigenesis in ESCC and LINC00022, specific target of m6A, serves as a potential biomarker for this malignancy.

| S-EPMC8451109 | biostudies-literature

Post-translational modification of RNA m6A demethylase ALKBH5 regulates ROS-induced DNA damage response.

Project description:Faithful genome integrity maintenance plays an essential role in cell survival. Here, we identify the RNA demethylase ALKBH5 as a key regulator that protects cells from DNA damage and apoptosis during reactive oxygen species (ROS)-induced stress. We find that ROS significantly induces global mRNA N6-methyladenosine (m6A) levels by modulating ALKBH5 post-translational modifications (PTMs), leading to the rapid and efficient induction of thousands of genes involved in a variety of biological processes including DNA damage repair. Mechanistically, ROS promotes ALKBH5 SUMOylation through activating ERK/JNK signaling, leading to inhibition of ALKBH5 m6A demethylase activity by blocking substrate accessibility. Moreover, ERK/JNK/ALKBH5-PTMs/m6A axis is activated by ROS in hematopoietic stem/progenitor cells (HSPCs) in vivo in mice, suggesting a physiological role of this molecular pathway in the maintenance of genome stability in HSPCs. Together, our study uncovers a molecular mechanism involving ALKBH5 PTMs and increased mRNA m6A levels that protect genomic integrity of cells in response to ROS.

| S-EPMC8191756 | biostudies-literature

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