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Targeting FTO suppresses cancer stem cell maintance and immune evasion

ABSTRACT: Targeting FTO suppresses cancer stem cell maintance and immune evasion

PROVIDER: PRJNA606960 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11093922.fastq.gz	Fastqsanger.gz
	SRR11093923.fastq.gz	Fastqsanger.gz
	SRR11093924.fastq.gz	Fastqsanger.gz
	SRR11093925.fastq.gz	Fastqsanger.gz

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Targeting FTO suppresses cancer stem cell maintance and immune evasion

Project description:We conducted RNA sequencing with poly A RNA isolated from spleen mononuclear cells of MLL-AF9 (MA9) mouse models after treatment with PBS and FTO inhibitor CS1.

2020-04-11 | GSE145363 | GEO

Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion.

Project description:Fat mass and obesity-associated protein (FTO), an RNA N6-methyladenosine (m6A) demethylase, plays oncogenic roles in various cancers, presenting an opportunity for the development of effective targeted therapeutics. Here, we report two potent small-molecule FTO inhibitors that exhibit strong anti-tumor effects in multiple types of cancers. We show that genetic depletion and pharmacological inhibition of FTO dramatically attenuate leukemia stem/initiating cell self-renewal and reprogram immune response by suppressing expression of immune checkpoint genes, especially LILRB4. FTO inhibition sensitizes leukemia cells to T cell cytotoxicity and overcomes hypomethylating agent-induced immune evasion. Our study demonstrates that FTO plays critical roles in cancer stem cell self-renewal and immune evasion and highlights the broad potential of targeting FTO for cancer therapy.

| S-EPMC7363590 | biostudies-literature

Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance

Project description:Ever-increasing understanding about the complexity of factors and regulatory layers that contribute to immune evasion facilitates the development of immunotherapies. However, the diversity of malignant tumors limits many known mechanisms in specific genetic and epigenetic contexts, manifesting the need to discover general driver genes. Here, we have identified the m6A demethylase FTO as an essential epitranscriptomic regulator utilized by tumors to escape immune surveillance through regulation of glycolytic metabolism. We show that FTO-mediated m6A demethylation in tumor cells elevates transcription factors c-Jun, JunB, and C/EBPβ, which allows the rewiring of glycolytic metabolism. Fto knockdown impairs the glycolytic activity of tumor cells, which restores the function of CD8+ T cells, thereby inhibiting tumor growth. Furthermore, we developed a small-molecule compound Dac51 that can inhibit the activity of FTO, block FTO-mediated immune evasion, and synergize with checkpoint blockade for better tumor control, suggesting reprogramming RNA epitranscriptome as a potential strategy for immunotherapy.

2021-04-30 | GSE154952 | GEO

Targeting FTO suppresses hepatocellular carcinoma by inhibiting ERBB3 and TUBB4A expression [MeRIP]

Project description:Targeting FTO suppresses hepatocellular carcinoma by inhibiting ERBB3 and TUBB4A expression [MeRIP]

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An HIV protein mediates immune evasion by targeting cGAS–STING signaling

Project description:The cyclic GMP-AMP synthase (cGAS) recognizes Y-form cDNA of HIV-1 and initiate the antiviral immune response through cGAS–STING–TBK1–IRF3–type I IFN (IFN-I) signaling cascade. HIV-1 uses several strategies to interfere with the host immune molecules and mediate immune evasion. However, the potential role of HIV-1 proteins in cGAS–STING signaling remains unclear. Here we report that the HIV-1 protein p6 suppresses HIV-1-stimulated expression of IFN-I and promotes the immune evasion. Mechanistically, p6 bound with STING and inhibited the activation of STING and the interaction between STING and TBK1. Moreover, the glutamylation of p6 at Glu6 residue inhibited the interaction between STING and TRIM32 or AMFR, which subsequently suppressed the K27- and K63-linked polyubiquitination of STING at Lys337, therefore inhibited STING activation and type I IFN production, while the mutation of Glu6 residue lost the inhibitory effect. However, CoCl2, an agonist for cytosolic carboxypeptidases (CCPs), counteracted the glutamylation of Glu6 residue of p6 and promoted IFN-I production to block the immune evasion of HIV-1. These findings not only reveal a previously unknown mechanism through which an HIV-1 protein mediate immune evasion, but also provide a new therapeutic drug candidate to treat HIV-1 infection.

2021-11-25 | GSE189384 | GEO

Targeting FTO suppresses hepatocellular carcinoma by inhibiting ERBB3 and TUBB4A expression [MeRIP]

Project description:Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase and plays a critical oncogenic role in various cancers. Here we show that FTO is an effective target in hepatocellular carcinoma (HCC). FTO is highly expressed in clinical patients of HCC and presents as a poor prognostic factor. Genetic depletion of FTO dramatically attenuated HCC progression in vivo. Pharmacological inhibition of FTO by FB23/FB23-2 remarkably suppressed the proliferation and migration of HCC cell lines in vitro, as well as inhibiting the HCC tumorigenicity in xeno-transplanted mice. Mechanistically, FB23-2 suppressed the expression of Erb-b2 receptor tyrosine kinase 3 (ERBB3) and human tubulin beta class Iva (TUBB4A) by increasing the m6A level in these mRNA transcripts. The decreased ERBB3 resulted in inhibited Akt-mTOR signaling that subsequently impaired the proliferation and survival of HCC cells. Moreover, FB23-2 abolished the organization of the tubulin cytoskeleton, while enforced expression of TUBB4A rescued the migration of HCC cells. Collectively, our study demonstrated that FTO plays a critical role in HCC by maintaining the proliferation and migration of cells, and highlights the broad potential of FTO inhibitors for targeting HCC.

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Targeting FTO suppresses hepatocellular carcinoma by inhibiting ERBB3 and TUBB4A expression [RNA-seq]

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Targeting FTO suppresses hepatocellular carcinoma by inhibiting ERBB3 and TUBB4A expression [RNA-seq]

Project description:Targeting FTO suppresses hepatocellular carcinoma by inhibiting ERBB3 and TUBB4A expression [RNA-seq]

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An HIV protein mediates immune evasion by targeting cGAS–STING signaling

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Oncogenic RAD21 Amplification Suppresses Interferon Signalling to Promote Immune Evasion in Ovarian Cancer

Project description:Oncogenic RAD21 Amplification Suppresses Interferon Signalling to Promote Immune Evasion in Ovarian Cancer

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