The role of m6A modification in the biological functions and diseases

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Feb. 21, 2021

Abstract N 6 -methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher cells. m6A modified by methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, KIAA1429, and, removed demethylases, erasers, including FTO ALKBH5. It recognized m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 HNRNPA2B1, also known “readers”. Recent studies have shown that RNA plays essential role both physiological pathological conditions, initiation progression of different types human cancers. In this review, we discuss how methylation influences progressions hematopoietic, central nervous reproductive systems. We will mainly focus on recent progress identifying biological functions underlying molecular mechanisms methylation, its regulators downstream target genes, during cancer above propose process offer potential targets for therapy future.

Language: Английский

---

m6A Modification in Coding and Non-coding RNAs: Roles and Therapeutic Implications in Cancer

Cancer Cell, Journal Year: 2020, Volume and Issue: 37(3), P. 270 - 288

Published: March 1, 2020

Language: Английский

---

The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation

Nucleic Acids Research, Journal Year: 2020, Volume and Issue: 48(7), P. 3816 - 3831

Published: Jan. 22, 2020

Abstract N 6-Methyladenosine (m6A) is the most abundant RNA modification in mammal mRNAs and increasing evidence suggests key roles of m6A human tumorigenesis. However, whether m6A, especially its ‘reader’ YTHDF1, targets a gene involving protein translation thus affects overall production cancer cells largely unexplored. Here, using multi-omics analysis for ovarian cancer, we identified novel mechanism EIF3C, subunit initiation factor EIF3, as direct target YTHDF1. YTHDF1 augments EIF3C an m6A-dependent manner by binding to m6A-modified mRNA concomitantly promotes translational output, thereby facilitating tumorigenesis metastasis cancer. frequently amplified up-regulation associated with adverse prognosis patients. Furthermore, but not abundance increased positively correlates expression patients, suggesting more relevant role Collectively, identify YTHDF1-EIF3C axis critical progression which can serve develop therapeutics treatment.

Language: Английский

---

Histone lactylation drives oncogenesis by facilitating m6A reader protein YTHDF2 expression in ocular melanoma

Genome biology, Journal Year: 2021, Volume and Issue: 22(1)

Published: March 16, 2021

Histone lactylation, a metabolic stress-related histone modification, plays an important role in the regulation of gene expression during M1 macrophage polarization. However, lactylation tumorigenesis remains unclear.Here, we show is elevated tumors and associated with poor prognosis ocular melanoma. Target correction aberrant triggers therapeutic efficacy both vitro vivo. Mechanistically, contributes to by facilitating YTHDF2 expression. Moreover, recognizes m6A modified PER1 TP53 mRNAs promotes their degradation, which accelerates melanoma.We reveal oncogenic thereby providing novel targets for melanoma therapy. We also bridge modifications RNA modifications, provides understanding epigenetic tumorigenesis.

Language: Английский

---

The role of m6A RNA methylation in cancer metabolism

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: Jan. 12, 2022

Abstract Metabolic reprogramming is one of the main characteristics malignant tumors, which due to flexible changes cell metabolism that can meet needs growth and maintain homeostasis tissue environments. Cancer cells obtain metabolic adaptation through a variety endogenous exogenous signaling pathways, not only promote cancer cells, but also start transformation process adapt tumor microenvironment. Studies show m6A RNA methylation widely involved in recombination cells. In eukaryotes, most abundant modification mRNA, almost all cycle stages, including regulation transcription, maturation, translation, degradation stability mRNA. M6A be physiological pathological processes, cancer. this review, we discuss role plays metabolism-related molecules aiming importance targeting regulating metabolism.

Language: Английский

---

HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Feb. 23, 2021

Abstract N6-methyladenosine (m6A), and its reader protein YTHDF1, play a pivotal role in human tumorigenesis by affecting nearly every stage of RNA metabolism. Autophagy activation is one the ways which cancer cells survive hypoxia. However, possible involvement m6A modification mRNA hypoxia-induced autophagy was unexplored hepatocellular carcinoma (HCC). In this study, specific variations YTHDF1 expression were detected YTHDF1-overexpressing, -knockout, -knockdown HCC cells, organoids, patient-derived xenograft (PDX) murine models. significantly correlated vitro; significant overexpression tissues associated with poor prognosis. Multivariate cox regression analysis identified as an independent prognostic factor patients HCC. Multiple models confirmed that deficiency inhibited autophagy, growth, metastasis. Luciferase reporter assays chromatin immunoprecipitation demonstrated HIF-1α regulated transcription directly binding to promoter region under The results methylated sequencing, proteomics, polysome profiling indicated contributed translation autophagy-related genes ATG2A ATG14 m6A-modified mRNA, thus facilitating malignancy Taken together, HIF-1α-induced progression via promoting m6A-dependent manner. Our findings suggest potential biomarker therapeutic target for

Language: Английский

---

m6A modification: recent advances, anticancer targeted drug discovery and beyond

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: Feb. 14, 2022

Abstract Abnormal N6-methyladenosine (m6A) modification is closely associated with the occurrence, development, progression and prognosis of cancer, aberrant m6A regulators have been identified as novel anticancer drug targets. Both traditional medicine-related approaches modern discovery platforms used in an attempt to develop m6A-targeted drugs. Here, we provide update latest findings on critical roles cancer progression, summarize rational sources for agents from medicines computer-based chemosynthetic compounds. This review highlights potential targeting treatment proposes advantage artificial intelligence (AI) m6A-targeting Graphical abstract Three stages discovery: medicine-based natural products, chemical or synthesis, (AI)-assisted future.

Language: Английский

---

m6A-binding proteins: the emerging crucial performers in epigenetics

Journal of Hematology & Oncology, Journal Year: 2020, Volume and Issue: 13(1)

Published: April 10, 2020

Abstract N 6 -methyladenosine (m A) is a well-known post-transcriptional modification that the most common type of methylation in eukaryotic mRNAs. The regulation m A dynamic and reversible, which erected by methyltransferases (“writers”) removed demethylases (“erasers”). Notably, effects on targeted mRNAs resulted predominantly depend functions different A-binding proteins (“readers”) including YT521-B homology (YTH) domain family, heterogeneous nuclear ribonucleoproteins (HNRNPs), insulin-like growth factor 2 mRNA-binding (IGF2BPs). Indeed, readers not only participate multiple procedures RNA metabolism, but also are involved variety biological processes. In this review, we summarized specific underlying mechanisms tumorigenesis, hematopoiesis, virus replication, immune response, adipogenesis.

Language: Английский

---

Role of m6A RNA methylation in cardiovascular disease (Review)

International Journal of Molecular Medicine, Journal Year: 2020, Volume and Issue: 46(6), P. 1958 - 1972

Published: Oct. 6, 2020

N6‑methyladenosine (m6A) is the most prevalent and abundant type of internal post‑transcriptional RNA modification in eukaryotic cells. Multiple types RNA, including mRNAs, rRNAs, tRNAs, long non‑coding RNAs microRNAs, are involved m6A methylation. The biological function dynamically reversibly mediated by methyltransferases (writers), demethylases (erasers) binding proteins (readers). methyltransferase complex responsible for catalyzation typically made up methyltransferase‑like (METTL)3, METTL14 Wilms tumor 1‑associated protein. Erasers remove methylation fat mass obesity‑associated protein ALKB homolog 5. Readers play a role through recognition m6A‑modified targeted RNA. YT521‑B homology domain family, heterogeneous nuclear ribonucleoprotein insulin‑like growth factor 2 mRNA‑binding serve as readers. on transcripts plays pivotal regulation downstream molecular events functions, such splicing, transport, stability translatability at level. dysregulation associated with cancer, drug resistance, virus replication pluripotency embryonic stem Recently, number studies have identified aberrant cardiovascular diseases (CVDs), cardiac hypertrophy, heart failure, arterial aneurysm, vascular calcification pulmonary hypertension. aim present review article was to summarize recent research progress CVD give brief perspective its prospective applications CVD.

Language: Английский

---

N6-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells

Redox Biology, Journal Year: 2021, Volume and Issue: 47, P. 102151 - 102151

Published: Sept. 27, 2021

Ferroptosis is a recently identified non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation. However, the underlying exact mechanisms remain poorly understood. Here, we report that total levels N6-methyladenosine (m6A) modification are evidently increased upon exposure to ferroptosis-inducing compounds due upregulation methylase METTL4 and downregulation demethylase FTO. Interestingly, RNA-seq shows m6A appears trigger autophagy activation stabilizing BECN1 mRNA, which may be potential mechanism for modification-enhanced HSC ferroptosis. Importantly, YTHDF1 as key reader protein mRNA stability, knockdown could prevent plasmid-induced Noteworthy, promotes stability via recognizing binding site within coding regions. In mice, erastin treatment alleviates liver fibrosis inducing HSC-specific inhibition impair erastin-induced ferroptosis in murine fibrosis. Moreover, retrospectively analyzed effect sorafenib on advanced fibrotic patients with hepatocellular carcinoma (HCC) receiving monotherapy. Attractively, upregulation, activation, induction occur human HSCs. Overall, these findings reveal novel signaling pathways molecular ferroptosis, also identify modification-dependent target

Language: Английский

---