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

и другие.

Advanced Science, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 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.

Язык: Английский

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

Biochemical Society Transactions, Год журнала: 2024, Номер 52(2), С. 707 - 717

Опубликована: Апрель 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.

Язык: Английский

Процитировано

10
RNA Binding by the m6A Methyltransferases METTL16 and METTL3 DOI Creative Commons
Kyle D. Mansfield

Biology, Год журнала: 2024, Номер 13(6), С. 391 - 391

Опубликована: Май 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.

Язык: Английский

Процитировано

6
Crosstalk between N6-methyladenosine modification and ncRNAs in rheumatic diseases: therapeutic and diagnostic implications DOI
Jianting Wen, Jian Liu,

Lei Wan

и другие.

Inflammation Research, Год журнала: 2025, Номер 74(1)

Опубликована: Май 22, 2025

Язык: Английский

Процитировано

0
Novel Insights into the Regulatory Role of N6-Methyladenosine in the Pathogenesis and Clinical Treatment of Osteoarthritis: Research Status and Prospect DOI Creative Commons
Mingyu He, Jian Liu, Yanqiu Sun

и другие.

Journal of Inflammation Research, Год журнала: 2025, Номер Volume 18, С. 6749 - 6766

Опубликована: Май 1, 2025

Osteoarthritis (OA) is caused by characteristic joint tissue lesions characterized chronic pain, stiffness, and limited mobility. OA one of the most common causes disability in adults, seriously affecting quality life patients causing huge medical socio-economic burdens. N6-methyladenosine (m6A) a methylation that occurs at N6 position adenosine chemical modification on eukaryotic RNA. m6A dynamic regulation process involving "writers" (methyltransferases), "erasers" (demethylases), "readers" (reading proteins). Disruption or interference this may lead to dysregulation cellular regulatory mechanisms, resulting various diseases. This article summarized mechanism pathogenesis, including inflammatory response immune infiltration, extracellular matrix (ECM) degradation, programmed cell death, bone homeostasis, osteogenic differentiation. Finally, application future development prospects clinical treatment were further discussed.

Язык: Английский

Процитировано

0
YTHDFs as radiotherapy checkpoints in tumor immunity DOI
Chuangyu Wen, Emile Naccasha, Chuan He

и другие.

The Journal of Experimental Medicine, Год журнала: 2025, Номер 222(8)

Опубликована: Июнь 5, 2025

Radiotherapy (RT), a cornerstone of cancer treatment, exerts its therapeutic effects primarily by inducing DNA damage in tumor cells and modulating the immune microenvironment (TIME). Despite efficacy, RT is often counteracted tumor-intrinsic mechanisms, such as repair, well immune-suppressive responses. YTHDF proteins, key N6-methyladenosine (m6A) readers, have emerged pivotal regulators progression, cell function, making them promising targets for enhancing efficacy. In this review, we explore dual roles proteins both immune-mediated responses to RT. We summarize their influence on repair pathways impact TIME, which collectively shape antitumor efficacy Furthermore, discuss recent advances development YTHDF-targeting inhibitors potential synergize with immunotherapy, offering new avenues improve treatment outcomes.

Язык: Английский

Процитировано

0
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, Год журнала: 2024, Номер 87, С. 102224 - 102224

Опубликована: Июль 8, 2024

N

Язык: Английский

Процитировано

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

Yuyan,

Enwu Yuan

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Сен. 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

Язык: Английский

Процитировано

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

и другие.

NAR Cancer, Год журнала: 2024, Номер 6(3)

Опубликована: Июль 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.

Язык: Английский

Процитировано

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

и другие.

EMBO Reports, Год журнала: 2024, Номер 25(12), С. 5265 - 5276

Опубликована: Ноя. 19, 2024

Язык: Английский

Процитировано

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

и другие.

Advanced Science, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 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.

Язык: Английский

Процитировано

0