RNA m6A reader YTHDF2 facilitates lung adenocarcinoma cell proliferation and metastasis by targeting the AXIN1/Wnt/ β-catenin signaling
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ABSTRACT:
PROVIDER: PRJNA675539 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13010455_1.fastq.gz | Fastqsanger.gz | |||
| SRR13010455_2.fastq.gz | Fastqsanger.gz | |||
| SRR13010456_1.fastq.gz | Fastqsanger.gz | |||
| SRR13010456_2.fastq.gz | Fastqsanger.gz | |||
| SRR13010457_1.fastq.gz | Fastqsanger.gz |
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Project description:Lung cancer is a leading cause of cancer-related mortality worldwide and poor prognosis remains a major problem encountered in its treatment. The dynamic and reversible N6-methyladenosine (m6A) RNA modification has been recently implicated in the tumorigenesis and metastasis of a variety of cancers. However, the biological functions and underlying mechanisms of YTHDF2 in the regulation of lung adenocarcinoma (LUAD) progression remain elusive. Here we report that YTHDF2 expression was significantly increased in lung adenocarcinoma than in adjacent normal tissues. YTHDF2 knockdown drastically inhibited cell proliferation, colony formation, and migration in vitro, and the opposite proved true when YTHDF2 was overexpressed. In addition, YTHDF2 attenuation significantly inhibited tumorigenesis in a murine tumor xenograft model. Through the integrative analysis of RNA-seq, m6A-seq, CLIP-seq, and RIP-seq datasets, we identified a set of potential direct targets of YTHDF2 in lung adenocarcinoma. We further confirmed AXIN1, which encodes a negative regulator of the Wnt/β-catenin signaling, as a direct target of YTHDF2. YTHDF2 promotes AXIN1 RNA decay and subsequently activates the Wnt/β-catenin signaling. Knockout of AXIN1 can sufficiently rescue the inhibitory effect of YTHDF2 depletion on lung cancer cell proliferation, colony-formation, and migration. Collectively, our results uncovered YTHDF2-mediated regulation of the AXIN1/Wnt/β-catenin signaling that contributes to LUAD tumorigenesis, and thus provided insight into the mechanisms underlying lung adenocarcinoma progression.
2021-05-19 | GSE161090 | GEO
Project description:The transcription factor RUNX1 exhibits recurrent loss-of-function mutations in estrogen receptor-positive (ER+) breast cancer (BCa). Its knockdown in vitro decreased AXIN1 expression in estrogen-dependent manner. Consistently, RUNX1 and AXIN1 mRNA levels are strongly correlated in ER+, not ER- tumors. RUNX1 occupies AXIN1â??s second intron in living cells, abutting an ERa-binding site. Potentially promoting BCa progression, decreased AXIN1 expression after RUNX1 knockdown associated with upregulation of b-catenin, and this was preventable by AXIN stabilizers. Unlike in colon cancer, however, deregulation of b-catenin in BCa cells affect neither c-Myc, nor CCND1, nor G1/S cell cycle phase transition. Instead, cyclin B1 was decreased and the G2/M checkpoint was compromised as indicated by mitotic slippage in the presence of microtubule disruptors. Thus, combined analysis of the RUNX1 transcriptome, its cistrome, and differential mRNA expression in tumors with wild type versus mutant RUNX1, altogether highlight a role for the RUNX1/AXIN1/b-catenin axis in ER+ BCa. Significance: Three recent exome sequencing studies assigned to RUNX1 a BCa suppressor role. The present study begins to uncover the underlying molecular mechanisms, offers an explanation for the specificity to ER+ tumors, and marks AXIN1 as a therapeutic target for ER+/RUNX1- BCa. Examination of RUNX1 binding in MCF7 cells
2016-02-22 | E-GEOD-65313 | biostudies-arrayexpress
Project description:The transcription factor RUNX1 exhibits recurrent loss-of-function mutations in estrogen receptor-positive (ER+) breast cancer (BCa). Its knockdown in vitro decreased AXIN1 expression in estrogen-dependent manner. Consistently, RUNX1 and AXIN1 mRNA levels are strongly correlated in ER+, not ER- tumors. RUNX1 occupies AXIN1’s second intron in living cells, abutting an ERa-binding site. Potentially promoting BCa progression, decreased AXIN1 expression after RUNX1 knockdown associated with upregulation of b-catenin, and this was preventable by AXIN stabilizers. Unlike in colon cancer, however, deregulation of b-catenin in BCa cells affect neither c-Myc, nor CCND1, nor G1/S cell cycle phase transition. Instead, cyclin B1 was decreased and the G2/M checkpoint was compromised as indicated by mitotic slippage in the presence of microtubule disruptors. Thus, combined analysis of the RUNX1 transcriptome, its cistrome, and differential mRNA expression in tumors with wild type versus mutant RUNX1, altogether highlight a role for the RUNX1/AXIN1/b-catenin axis in ER+ BCa. Significance: Three recent exome sequencing studies assigned to RUNX1 a BCa suppressor role. The present study begins to uncover the underlying molecular mechanisms, offers an explanation for the specificity to ER+ tumors, and marks AXIN1 as a therapeutic target for ER+/RUNX1- BCa.
2016-02-22 | GSE65313 | GEO
Project description:Aberrant activation of Wnt/β-catenin signaling is observed in numerous cancers. In hepatocellular carcinoma activating mutations in CTNNB1 (20-25%) or loss of function mutations in AXIN1 (10%), AXIN2 (2%) and APC (1-2%) are observed. All these mutations lead to aberrant stabilization of β-catenin, which constitutively activates downstream Wnt/β-catenin target genes and triggers a genetic program resulting in tumor formation. However, in relation to AXIN1 mutations some reports have challenged whether these indeed result in tumor growth by enhancing β-catenin signaling (e.g. PMID: 16964294, 29525529). Several alternative pathways have also been linked to AXIN1 (ENSG00000103126), such as TGFβ, SAPK/JNK, p53, YAP/TAZ and c-myc. To identify which one of these or other unknown signaling routes are linked to AXIN1, using CRISPR-Cas9 genome editing, we have successfully repaired the homozygous p.R712* AXIN1 mutation present in the SNU449 hepatocellular carcinoma cell line. Next, using RNA sequencing the RNA expression patterns of 3 independent repaired clones were compared with 3 clones retaining the AXIN1 mutation. Surprisingly, only 5 genes were significantly altered in the repaired clones, among which AXIN2, a well-established β-catenin target gene. Thus, this analysis leads to the surprising observation that a commonly observed mutation in a hepatocellular tumor suppressor gene, is associated with minimal alterations in gene expression, at least in the SNU449 cell line.
2019-01-01 | GSE119001 | GEO
Project description:Tumors evade attacks from the immune system through various mechanisms. Here, we identify a component of tumor immune evasion mediated by YTH domain-containing family protein 2 (YTHDF2), a reader protein that usually destabilizes m6A-modified mRNA. Loss of tumoral YTHDF2 inhibits tumor growth and prolongs survival in immunocompetent tumor models. Mechanistically, tumoral YTHDF2 deficiency promotes the recruitment of macrophages via CX3CL1 and enhances mitochondrial respiration of CD8+ T cells by impairing tumor glycolysis metabolism. Tumoral YTHDF2 deficiency promotes inflammatory macrophage polarization and antigen presentation in the presence of IFN-γ. In addition, IFN-γ induces autophagic degradation of tumoral YTHDF2, thereby sensitizing tumor cells to CD8+ T cell-mediated cytotoxicity. Last, we identified a small molecule compound that preferentially induces YTHDF2 degradation, which shows a potent antitumor effect alone but a better effect when combined with anti-PD-L1 or anti-PD-1 antibodies. Collectively, YTHDF2 appears to be a tumor-intrinsic regulator that orchestrates immune evasion, representing a promising target for enhancing cancer immunotherapy.
2024-05-31 | GSE239426 | GEO
Project description:Tumors evade attacks from the immune system through various mechanisms. Here, we identify a component of tumor immune evasion mediated by YTH domain-containing family protein 2 (YTHDF2), a reader protein that usually destabilizes m6A-modified mRNA. Loss of tumoral YTHDF2 inhibits tumor growth and prolongs survival in immunocompetent tumor models. Mechanistically, tumoral YTHDF2 deficiency promotes the recruitment of macrophages via CX3CL1 and enhances mitochondrial respiration of CD8+ T cells by impairing tumor glycolysis metabolism. Tumoral YTHDF2 deficiency promotes inflammatory macrophage polarization and antigen presentation in the presence of IFN-γ. In addition, IFN-γ induces autophagic degradation of tumoral YTHDF2, thereby sensitizing tumor cells to CD8+ T cell-mediated cytotoxicity. Last, we identified a small molecule compound that preferentially induces YTHDF2 degradation, which shows a potent antitumor effect alone but a better effect when combined with anti-PD-L1 or anti-PD-1 antibodies. Collectively, YTHDF2 appears to be a tumor-intrinsic regulator that orchestrates immune evasion, representing a promising target for enhancing cancer immunotherapy.
2024-05-31 | GSE239423 | GEO
Project description:Dynamic N6-methyladenosine (m6A) modification was previously identified as a ubiquitous post-transcriptional regulation that affected mRNA homeostasis. However, the m6A-related epitranscriptomic alterations and functions remain elusive in human diseases such as cancer. Here we show that hypoxia regulates the ‘reader’ protein YTH domain family 2 (YTHDF2), to eventually stabilize the methylated oncogene mRNAs in inflammation-associated liver cancer. YTHDF2 silenced in human cancer cells or depleted in mouse hepatocytes evoked pro-inflammatory responses and accelerated tumor growth and metastatic progression. Under hypoxia, YTHDF2 processed the decay of m6A-containing interleukin 11 (IL11) and serpin family E member 2 (SERPINE2) mRNAs, which were responsible for the inflammation-mediated malignancy. Reciprocally, YTHDF2 transcription succumbed to hypoxia-inducible factor-2α (HIF-2α). Administration of a HIF-2α antagonist (PT2385) restored YTHDF2-programed epigenetic machinery and repressed liver cancer. Hence, our findings provide a new insight into the mechanism by which hypoxia adapts m6A-mRNA editing to promote cancer.
2020-03-17 | GSE120860 | GEO
Project description:As the most abundant glial cells in the CNS, astrocytes dynamically respond to neurotoxic stress, however, the key molecular regulators controlling the inflammatory status of these sentinels during neurotoxic stress have remained elusive. Herein, we demonstrate that the m6A epitranscriptomic mRNA modification tightly regulates the pro-inflammatory functions of astrocytes. Specifically, the astrocytic neurotoxic stresser, manganese (Mn), downregulated the m6A reader YTHDF2 in human and mouse astrocyte cultures and in the mouse brain. Functionally, YTHDF2 knockdown augmented, while its overexpression dampened, neurotoxic stress induced proinflammatory response, suggesting YTHDF2 serves as a key upstream regulator of inflammatory responses in astrocytes. Mechnistically, YTHDF2 RIP-sequencing identified MAP2K4 (MKK4; SEK1) mRNA as a YTHDF2 target influencing inflammatory signaling. Our target validation revealed Mn-exposed astrocytes mediates proinflammatory response by activating the phosphorylation of SEK1, JNK, and cJUN signaling. Collectively, YTHDF2 serves a key upstream ‘molecular switch’ controlling SEK1(MAP2K4)-JNK-cJUN proinflammatory signaling in astrocytes.
2024-07-19 | GSE254720 | GEO
Project description:Tumors evade attacks from the immune system through various mechanisms. Here, we identify a component of tumor immune evasion mediated by YTH domain-containing family protein 2 (YTHDF2), a reader protein that usually destabilizes m6A-modified mRNA. Loss of tumoral YTHDF2 inhibits tumor growth and prolongs survival in immunocompetent tumor models. Mechanistically, tumoral YTHDF2 deficiency promotes the recruitment of macrophages via CX3CL1 and enhances mitochondrial respiration of CD8+ T cells by impairing tumor glycolysis metabolism. Tumoral YTHDF2 deficiency promotes inflammatory macrophage polarization and antigen presentation in the presence of IFN-γ. In addition, IFN-γ induces autophagic degradation of tumoral YTHDF2, thereby sensitizing tumor cells to CD8+ T cell-mediated cytotoxicity. Last, we identified a small molecule compound that preferentially induces YTHDF2 degradation, which shows a potent antitumor effect alone but a better effect when combined with anti-PD-L1 or anti-PD-1 antibodies. Collectively, YTHDF2 appears to be a tumor-intrinsic regulator that orchestrates immune evasion, representing a promising target for enhancing cancer immunotherapy.
2024-05-31 | GSE256058 | GEO
Project description:N6-methyladenosine (m6A) is the most prevalent post-transcriptional modification on RNA. NK cells are the predominant innate lymphoid cells that mediate anti-viral and anti-tumor immunity. However, whether and how m6A modifications affect NK cell immunity remains unknown. Here, we discover that YTHDF2, a well-known m6A reader, is upregulated in NK cells upon activation by cytokines, tumors, and cytomegalovirus infection. Ythdf2 deficiency in NK cells impairs NK cell anti-tumor and anti-viral activity in vivo. YTHDF2 maintains NK cell homeostasis and terminal maturation, correlating with modulating NK cell trafficking and regulating Eomes, respectively. YTHDF2 promotes NK cell effector function and is required for IL-15-mediated NK cell survival and proliferation by forming a STAT5-YTHDF2 positive feedback loop. Transcriptome-wide screening identifies Tardbp to be involved in cell proliferation or survival as a YTHDF2-binding target in NK cells. Collectively, we elucidate the biological roles of m6A modifications in NK cells and highlight a new direction to harness NK cell anti-tumor immunity.
2021-05-08 | GSE174027 | GEO