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The N6-methylation of adenosine (m6A) in FZD10 mRNA contributes to PARP inhibitor resistance

ABSTRACT: Chemical modifications of RNAs have emerged as a new layer of epigenetic gene regulation. N6-methyladenosine (m6A) is the most abundant chemical modification of messenger RNA (mRNA). The m6A modification affects RNA fate and functions such as RNA stability. Despite the high initial response rates to PARP inhibitors in BRCA1/2-mutated epithelial ovarian cancers (EOC), PARP inhibitor (PARPi) resistance remains a major challenge. The role of m6A modification in PARPi resistance has not previously been explored. Here we show that m6A modification of FZD10 mRNA contributes to PARPi resistance by upregulating the Wnt/-catenin pathway in BRCA-mutated EOC cells. Global m6A profile reveals a significant increase in m6A modification in FZD10 mRNA. This correlates with an increase in FZD10 mRNA stability and an upregulation of the Wnt/-catenin pathway in PARPi resistant cells. FZD10 knockdown or inhibition of the Wnt/-catenin sensitizes the resistant cells to PARPi. Mechanistically, downregulation of m6A demethylases FTO and ALKBH5 is sufficient to increase FZD10 mRNA m6A modification and reduce PARPi sensitivity, which correlates with an increase in homologous recombination activity. Moreover, PAPRi and Wnt/-catenin inhibitor showed synergistic suppression of growth of PAPRi resistant cells both in vitro and in vivo in a xenograft ovarian cancer mouse model. Our results show that m6A contributes to PAPRi resistance in BRCA-deficient EOC cells by upregulating the Wnt/-catenin pathway through stabilizing FZD10. They also suggest that inhibition of Wnt/-catenin pathway represents a potential strategy to overcome PARPi resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE119963 | GEO | 2019/09/14

REPOSITORIES: GEO

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MOV10 facilitates messenger RNA decay in an N6-methyladenosine (m6A)-dependent manner to maintain the mouse embryonic stem cells state

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2024-01-15 | GSE181821 | GEO

Integrated analysis of the transcriptome-wide m6A methylome in preeclampsia and healthy control placentas

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2020-08-24 | GSE143966 | GEO

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Project description:Poly (ADP-ribose) Polymerase (PARP) inhibitors (PARPi) are approved to treat recurrent ovarian cancer with BRCA1 or BRCA2 mutations, and as maintenance therapy for recurrent platinum sensitive ovarian cancer (BRCA wild-type or mutated) after treatment with platinum. However, the acquired resistance against PARPi remains a clinical hurdle. Our previous study has demonstrated that PARPi can enhance the Aldehyde dehydrogenase (ALDH) activity in ovarian cancer cells, mainly through inducing expression of ALDH1A1, an isoform of the ALDH family. In addition, an ALDH1A1 selective inhibitor can synergize with olaparib in killing EOC cells carrying BRCA2 mutation in both in vitro cell culture and the in vivo xenograft animal model. In order to elucidating the mechanism by which ALDH1A1 renders PARPi resistance to ovarian cancer, we performed RNA-seq analysis to identify genes whose expression can be regulated by ALDH1A1.

2023-07-19 | GSE226018 | GEO

The N6-methylation of adenosine (m6A) in FZD10 mRNA contributes to PARP inhibitor resistance

Project description:The N6-methylation of adenosine (m6A) in FZD10 mRNA contributes to PARP inhibitor resistance

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Wnt/β-catenin signaling mediates resistance of colorectal cancer cells to chemoradiotherapy

Project description:Activation of Wnt/β-catenin signaling plays a central role in the development and progression of colorectal cancer (CRC). Previously, we demonstrated that the Wnt transcription factor, TCF7L2, was overexpressed in primary rectal cancers that were resistant to chemoradiotherapy (CRT), and that TCF7L2 functionally mediates resistance of CRC cells to CRT. However, it remained unclear whether the resistance was mediated by a TCF7L2 inherent mechanism or Wnt/β-catenin signaling in general. We now show that silencing of β-catenin resulted in sensitization of the CRC cell lines LS1034, SW480, and SW837 to CRT, demonstrating a relationship between Wnt/β-catenin signaling and CRT resistance. To investigate the potential role of Wnt/β-catenin signaling in controlling therapeutic responsiveness, non-tumorigenic RPE-1 cells were stimulated with Wnt-3a, a physiological ligand at the Frizzled receptor, which significantly increased resistance to CRT. This effect could be recapitulated by overexpression of mutated, undegradable β-catenin (S33Y). Again, this resulted in a significantly boosted resistance of RPE-1 cells to CRT, which was abrogated by siRNA-mediated silencing of β-catenin. Consistent with these findings, we observed higher expression levels of active (unphosphorylated) β-catenin as well as increased TCF/LEF reporter activity in SW1463 cells that evolved radiation-resistance due to repeated radiation-treatment. Global gene expression profiling identified several altered pathways associated with treatment response as a consequence of Wnt/β-catenin pathway activation, sheading new light on PPARD signaling as a possible mechanism of Wnt mediated resistance. Hence, synergistic pathway inhibition of either Wnt and/or one of the downstream-pathways may represent a promising strategy to increase therapeutic responsiveness to CRT.

2017-05-01 | GSE97543 | GEO

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Project description:Wnt/β-catenin signaling is essential for intestinal stem cell homeostasis and aberrant activation of this signaling leads to tumorigenesis. Here we report a function of YTHDF1, an mRNA m6A reader, in mediating β-catenin hyperactivation. Wnt signaling promotes YTHDF1 expression at the translational level. YTHDF1 is dispensable for normal intestinal development in mice while essential for intestinal regeneration. Ythdf1 knockout reduces the stemness of intestinal stem cells, which blocks Wnt-driven tumorigenesis. Genome-wide analysis identifies a subset of Wnt signaling components regulated by YTHDF1 in an m6A-dependent manner. Moreover, we demonstrate that YTHDF1 promotes the translation of TCF7L2/TCF4 to augment β-catenin activation. Targeting YTHDF1 in the established tumors leads to tumor shrinkage and prolonged survival. Together, our studies uncover YTHDF1 as an integral regulator of Wnt signaling at the translational level during intestinal tumorigenesis, which might serve as a promising target for colorectal cancer therapy.

2019-08-31 | GSE136664 | GEO

RNA m6A methylation regulates sorafenib-resistance in liver cancer through FOXO3-mediated autophagy [m6A RIP-seq]

Project description:N6-methyladenosine (m6A) is a type of nucleotide modification abundant in mRNA, which regulates mRNA stability, splicing and translation. However, its physiological role in intratumoral microenvironment and drug resistancehave not been fully understood. We demonstrated that METTL3,a primary m6A methyltransferase, was significantly down-regulated in human sorafenib-resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promoted sorafenib-resistance and angiogenesis and exacerbated progression by activating autophagy-associated pathway. Mechanistically, we identified FOXO3 as a key downstream target of the METTL3-mediated m6A modification. The m6A modification of FOXO3 at the 3'-untranslated region increased FOXO3 mRNA stability. Analysis of clinical samples showed that METTL3levels aretightly correlated with FOXO3levels in patients with HCC, and suppression of FOXO3 predicted poor clinical outcomes. Importantly, METTL3-depletion significantly enhanced sorafenib-resistance of HCC via a METTL3-FOXO3 axis, whereasoverexpression of FOXO3 restored the m6A-dependent sorafenib-sensitivity. Collectively, our work revealedthe critical function of the METTL3-mediated m6A modification in HCC in hypoxic tumor microenvironment, and provided insights into the molecular mechanism of the m6A modification in the resistance of HCC to sorafenib therapy.

2020-04-03 | GSE143234 | GEO

RNA m6A methylation regulates sorafenib-resistance in liver cancer through FOXO3-mediated autophagy [RNA-seq]

2020-04-03 | GSE143233 | GEO

m6A RNA Methylation Is Regulated by MicroRNAs and Promotes Reprogramming to Pluripotency

Project description:N6-methyladenosine (m6A) has been recently identified as a conserved epitranscriptomic modification of eukaryotic mRNAs, but its features, regulatory mechanisms, and functions in cell reprogramming are largely unknown. Here, we report m6A modification profiles in the mRNA transcriptomes of four cell types with different degrees of pluripotency. Comparative analysis reveals several features of m6A, especially gene- and cell-type-specific m6A mRNA modifications. We also show that microRNAs (miRNAs) regulate m6A modification via a sequence pairing mechanism. Manipulation of miRNA expression or sequences alters m6A modification levels through modulating the binding of METTL3 methyltransferase to mRNAs containing miRNA targeting sites. Increased m6A abundance promotes the reprogramming of mouse embryonic fibroblasts (MEFs) to pluripotent stem cells; conversely, reduced m6A levels impede reprogramming. Our results therefore uncover a role for miRNAs in regulating m6A formation of mRNAs and provide a foundation for future functional studies of m6A modification in cell reprogramming. m6A-seq in ESC, iPSC, NSC and sertoli cells.

2015-03-10 | E-GEOD-52125 | biostudies-arrayexpress

Targeted deletion of astrocytic Nhe1 stimulates Wnt/β-catenin-mediated BBB repair and angiogenesis after ischemic stroke

Project description:Roles of reactive perivascular astrocytes in dysregulation of the blood-brain barrier (BBB) function and cerebral perfusion are not well defined. Here, we investigated transformation of reactive astrocyte function for vascular repair after ischemic stroke by targeted deletion of astrocytic Na+/H+ exchanger isoform 1 in Gfap-CreERT2+/-;Nhe1f/f (Nhe1 Astro-KO) mice. Control Gfap-CreERT2+/-;Nhe1f/f (wild-type) mice displayed BBB damage (elevated endothelial transcytosis and intracellular vesicles) and persistent cerebral hypoperfusion in an ischemic stroke model (transient middle cerebral artery occlusion). In contrast, Nhe1 Astro-KO mice exhibited significantly less endothelial transcytosis and vesicle formation, and increased angiogenesis and cerebral blood perfusion (CBF) post-stroke. Bulk RNA-sequencing transcriptome analysis of isolated GFAP+ reactive astrocytes from wild-type and Nhe1 Astro-KO ischemic brains revealed that ~177 genes were differentially upregulated, with the Wnt7a mRNA among the top upregulated genes, along with additional Wnt pathway genes (Wnt7b, Fzd9, Fzd10, and Ndp). Abundant Wnt7a/b and β-catenin protein expression was detected in cerebral vessels of Nhe1 Astro-KO ischemic brains but not in the wild-type brains. Selective activation of Wnt/β-catenin pathway in cerebral vessels of Nhe1 Astro-KO ischemic brains was further validated using the Wnt reporter line TCF/LEF::H2B-eGFP; Gfap-CreERT2+/-;Nhe1f/f mice. Lastly, the role of Wnt/β-catenin pathway in resistance of Nhe1 Astro-KO mice to stroke-mediated BBB damage was tested by administration of Wnt/β-catenin inhibitor XAV-939. Taken together, we report that transforming reactive astrocyte function by upregulating astrocytic Wnt/β-catenin signaling activity is a novel mechanism to reduce the BBB endothelial damage, stimulate vascular repair, and restore cerebral blood flow after ischemic stroke.

2020-12-08 | GSE145839 | GEO

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