RNA N6‐Methyladenosine‐Binding Protein YTHDFs Redundantly Attenuate Cancer Immunity by Downregulating IFN‐γ Signaling in Gastric Cancer DOI Creative Commons

Dongjun Jang,

Chanwoong Hwa, Seoyeon Kim

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 25, 2024

Abstract Immunotherapy holds potential as a treatment for gastric cancer (GC), though immune checkpoint inhibitor (ICI) resistance remains an obstacle. One mechanism involves defects in interferon‐γ (IFN‐γ) signaling, which IFN‐γ is linked to improved responsiveness ICIs. Herein, the roles of RNA N 6 ‐methyladenosine (m6A) modifications regulation signaling and ICIs are unveiled. The m6A‐binding protein YTH RNA‐binding F1 (YTHDF1) overexpressed GC tissues, correlating with suppression immunity poorer survival rates. YTHDF1 overexpression impaired cells, knockdown studies indicated redundant effects YTHDF2 YTHDF3 responsiveness. immunoprecipitation sequencing revealed YTHDFs directly target interferon regulatory factor 1 (IRF1) mRNA, master regulator leading reduced stability consequent downregulation signaling. Furthermore, mouse syngeneic tumor models, Ythdf1 depletion cells resulted growth increased tumor‐infiltrating lymphocytes, attributed augmentation Collectively, these findings highlight how modulate by influencing through IRF1 regulation, suggesting their viability therapeutic targets immunotherapy.

Language: Английский

RNA m6A modification, signals for degradation or stabilisation? DOI Creative Commons
Guifeng Wei

Biochemical Society Transactions, Journal Year: 2024, Volume and Issue: 52(2), P. 707 - 717

Published: April 17, 2024

The RNA modification N6-methyladenosine (m6A) is conserved across eukaryotes, and profoundly influences metabolism, including regulating stability. METTL3 METTL14, together with several accessory components, form a ‘writer’ complex catalysing m6A modification. Conversely, FTO ALKBH5 function as demethylases, rendering dynamic. Key to understanding the functional significance of its ‘reader' proteins, exemplified by YTH-domain-containing proteins (YTHDFs) canonical reader insulin-like growth factor 2 mRNA-binding (IGF2BPs) non-canonical reader. These play crucial role in determining stability: YTHDFs mainly promote mRNA degradation through different cytoplasmic pathways, whereas IGF2BPs maintain Additionally, YTHDC1 functions within nucleus degrade or protect certain m6A-containing RNAs, other readers also contribute stability regulation. Notably, regulates retrotransposon LINE1 and/or transcription via multiple mechanisms. However, conflicting observations underscore complexities underlying m6A's regulation depending upon sequence/structure context, developmental stage, cellular environment. Understanding interplay between regulatory elements pivotal deciphering multifaceted roles plays broader biology.

Language: Английский

Citations

7
RNA Binding by the m6A Methyltransferases METTL16 and METTL3 DOI Creative Commons
Kyle D. Mansfield

Biology, Journal Year: 2024, Volume and Issue: 13(6), P. 391 - 391

Published: May 29, 2024

Methyltransferases are a wide-ranging, yet well-conserved, class of molecules that have been found to modify wide variety substrates. Interest in RNA methylation has surged recent years with the identification major eukaryotic mRNA m6A methyltransferase METTL3. METTL16 also identified as an methyltransferase; however, much less is known about its targets and actions. Interestingly, addition their catalytic activities, both METTL3 “methylation-independent” functions, including translational regulation, which discovered. However, evidence suggests METTL16’s role RNA-binding protein may be more significant than currently recognized. In this review, we will introduce methylation, specifically m6A, enzymes responsible for deposition. We discuss varying roles these perform delve deeper into possible methylation-independent binding proteins. Finally, touch upon many open questions still remaining.

Language: Английский

Citations

5
Roles of N6-methyladenosine writers, readers and erasers in the mammalian germline DOI Creative Commons
Graeme Raymond Wells, Ramesh S. Pillai

Current Opinion in Genetics & Development, Journal Year: 2024, Volume and Issue: 87, P. 102224 - 102224

Published: July 8, 2024

N

Language: Английский

Citations

2
Regulatory effect of N6-methyladenosine on tumor angiogenesis DOI Creative Commons

Yuyan,

Enwu Yuan

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Sept. 4, 2024

Previous studies have demonstrated that genetic alterations governing epigenetic processes frequently drive tumor development and modifications in RNA may contribute to these alterations. In the 1970s, researchers discovered N6-methyladenosine (m

Language: Английский

Citations

2
Decoding the molecular symphony: interactions between the m6A and p53 signaling pathways in cancer DOI Creative Commons
Rachel Shoemaker, Mo-Fan Huang,

Ying-Si Wu

et al.

NAR Cancer, Journal Year: 2024, Volume and Issue: 6(3)

Published: July 9, 2024

Abstract The p53 tumor suppressor gene governs a multitude of complex cellular processes that are essential for anti-cancer function and whose dysregulation leads to aberrant transcription, activation oncogenic signaling cancer development. Although mutations can occur at any point in the genetic sequence, missense comprise majority observed cancers regardless whether mutation is germline or somatic. One biological process involved both mutant wild-type N6-methyladenosine (m6A) epitranscriptomic network, type post-transcriptional modification over half all eukaryotic mRNAs. Recently, significant number findings have demonstrated unique interactions between m6A network variety types, shedding light on previously uncharacterized connection causes dysregulation. Cross-talk readers, writers erasers has been shown impact induce formation by influencing various hallmarks. Here, this review aims summarize interplay epitranscriptome pathway, highlighting its effects tumorigenesis other hallmarks cancer, as well identifying therapeutic implications future.

Language: Английский

Citations

2
Regulating translation in aging: from global to gene-specific mechanisms DOI Creative Commons
Mathilde Solyga, Amitabha Majumdar, Florence Besse

et al.

EMBO Reports, Journal Year: 2024, Volume and Issue: 25(12), P. 5265 - 5276

Published: Nov. 19, 2024

Language: Английский

Citations

1
RNA N6‐Methyladenosine‐Binding Protein YTHDFs Redundantly Attenuate Cancer Immunity by Downregulating IFN‐γ Signaling in Gastric Cancer DOI Creative Commons

Dongjun Jang,

Chanwoong Hwa, Seoyeon Kim

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 25, 2024

Abstract Immunotherapy holds potential as a treatment for gastric cancer (GC), though immune checkpoint inhibitor (ICI) resistance remains an obstacle. One mechanism involves defects in interferon‐γ (IFN‐γ) signaling, which IFN‐γ is linked to improved responsiveness ICIs. Herein, the roles of RNA N 6 ‐methyladenosine (m6A) modifications regulation signaling and ICIs are unveiled. The m6A‐binding protein YTH RNA‐binding F1 (YTHDF1) overexpressed GC tissues, correlating with suppression immunity poorer survival rates. YTHDF1 overexpression impaired cells, knockdown studies indicated redundant effects YTHDF2 YTHDF3 responsiveness. immunoprecipitation sequencing revealed YTHDFs directly target interferon regulatory factor 1 (IRF1) mRNA, master regulator leading reduced stability consequent downregulation signaling. Furthermore, mouse syngeneic tumor models, Ythdf1 depletion cells resulted growth increased tumor‐infiltrating lymphocytes, attributed augmentation Collectively, these findings highlight how modulate by influencing through IRF1 regulation, suggesting their viability therapeutic targets immunotherapy.

Language: Английский

Citations

0