Abstract
N6-methyladenosine (m6A) stands as the most prevalent modified form of RNA in eukaryotes, pivotal in various biological processes such as regulating RNA stability, translation, and transcription. All members within the YT521-B homology (YTH) gene family are categorized as m6A reading proteins, capable of identifying and binding m6A modifications on RNA, thereby regulating RNA metabolism and functioning across diverse physiological processes. YTH domain-containing 2 (YTHDC2), identified as the latest member of the YTH family, has only recently started to emerge for its biological function. Numerous studies have underscored the significance of YTHDC2 in human physiology, highlighting its involvement in both tumor progression and non-tumor diseases. Consequently, this review aims to further elucidate the pathological mechanisms of YTHDC2 by summarizing its functions and roles in tumors and other diseases, with a particular focus on its downstream molecular targets and signaling pathways.
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Background
N6-methyladenosine (m6A), the predominant form of RNA modification, plays a crucial role in various cellular biological processes by regulating transcription, translation, stability, processing, splicing, and degradation of target RNA [1, 2]. The regulation of m6A modification primarily involves three key factors: methyltransferases (writers), demethylases (erasers), and m6A RNA-binding proteins (readers) [3]. These proteins are capable of adding, removing, and recognizing m6A modifications on RNA molecules, thereby altering RNA structure and function (Fig. 1) [4]. The addition of m6A methylation is primarily catalyzed by the m6A methyltransferase complex (MTC) [5], with methyltransferase like 3 (METTL3) and methyltransferase like 14 (METTL14 serving as crucial enzymes within this complex [6]. Additionally, cofactors such as Wilms tumor 1-associated protein (WTAP) and RNA-binding motif protein 15 (RBM15) are involved in m6A methylation [7], collectively working to recognize specific adenine bases on RNA and transfer methyl groups from S-adenosylmethionine (SAM) to RNA adenine, thus forming m6A methylation modification [8]. M6A demethylases primarily include fat mass and obesity-related protein (FTO) and alkylation repair homolog protein 5 (ALKBH5), which reduce m6A modification on RNA to unmodified adenine, thereby removing m6A methylation modification [82].
In summary, YTHDC2 emerges as a critical regulator in the human reproductive system, influencing germ cell development, function, and physiology through gene expression regulation and RNA processing mechanisms. Its role holds substantial implications for maintaining normal reproductive system function.
The role of YTHDC2 in the nervous system
Xu et al. found that reducing the expression of METTL3 or METTL 14 in neural stem cells (NSCs) significantly reduces the abundance of m6A, cell proliferation, and neuronal generation, while enhancing the differentiation of glial cells. Meanwhile, YTHDC2 promotes neuronal generation by promoting the stability and translation efficiency of m6A modified Lrp2 mRNA, which may reverse spatial memory decline and depressive like behavior, making it a promising antidepressant strategy [83]. YTHDC2 interacts with m6A modified HERV-H RNA, binds to the genomic site of LTR7/HERV-H, and recruits the DNA 5mC demethylase TET1 to prevent epigenetic silencing of LTR7/HERV-H. In human embryonic stem cells, the interaction between YTHDC2 and LTR7 inhibits neural differentiation [90].
The translation of the genome through the internal ribosome entry site (IRES) dependent mechanism is crucial in the process of hepatitis C virus (HCV) infection [91,92,93]. YTHDC2 can recognize m6A methylated adenosine at position nt 331 in the HCV RNA gene and support HCV IRES dependent translation under the synergistic effect of cellular La antigen. YTHDC2 plays an important role in the translation initiation dependent on HCV IRES, providing a potential novel therapeutic pathway for intervening in the process of HCV infection [27]. YTHDC2 and METTL3 jointly regulate the expression of adhesion molecule with Ig like domain 2 (AMIGO2), regulate the proliferation and invasion ability of rheumatoid arthritis synovial fibroblasts, and thereby affect the disease progression of rheumatoid arthritis [94].
The role of YTHDC2 in metabolic diseases
YTHDC2 plays a pivotal role in combating diabetic peripheral neuropathy (DPN) by enhancing mitochondrial metabolism. It does so by reducing KDM5B mRNA stability, thereby increasing SIRT3 expression, which in turn improves mitochondrial function, suggests YTHDC2 as a promising target for DPN treatment through mitochondrial metabolic reprogramming [95]. The expression of circYTHDC2 increases under high glucose conditions, and the knockout of circYTHDC2 significantly inhibits the proliferation and migration of vascular smooth muscle cells (VSMCs). YTHDC2 regulates the stability of circYTHDC2 through m6A modification, while circYTHDC2 negatively regulates the expression of TET2 by targeting the 3'UTR unstable motif of TET2, promoting the differentiation of VSMCs into synthetic ones [96]. These findings indicate that the YTHDC2/circYTHDC2/TET2 pathway is an important target for metformin to prevent the progression of high glucose induced VSMCs dysfunction. Zhou et al. found that the expression of YTHDC2 was significantly reduced in the liver of obese mice and non-alcoholic fatty liver disease (NAFLD) patients, and was associated with liver fat accumulation. Mechanistically, YTHDC2 can bind to the mRNA of lipid synthesis genes, thereby reducing their mRNA stability and inhibiting their gene expression [97]. This indicates that YTHDC2 also plays an important role in regulating liver lipid synthesis and triglyceride homeostasis, which has potential implications for the treatment of NAFLD associated with obesity. HIF1A is a transcription factor that can promote the browning process of adipocytes by activating the transcription of key thermogenic genes, and has potential therapeutic significance in combating obesity and metabolic diseases [98, 99]. The absence of FTO in adipose tissue leads to an increase in the m6A modification level of HIF1A mRNA, while YTHDC2 can promote the translation of HIF1A and increase the abundance of HIF1A protein in a m6A methylation dependent manner [100].
The role of YTHDC2 in other pathophysiological processes
CYP2C8 is a cytochrome P450 enzyme that plays an important role in drug metabolism [101, 102]. It mainly participates in the oxidative metabolism reaction of drugs, converting some drugs into more easily excreted metabolites, thereby affecting the metabolism and efficacy of drugs. CYP2C8 can be methylated with m6A by METTL3/14 in the liver and removed by FTO, while YTHDC2 recognizes m6A modified CYP2C8 mRNA and promotes its degradation, thereby regulating CYP2C8 expression and affecting drug metabolism [103]. Carboxyesterase 2 (CES2) is a serine esterase responsible for the hydrolysis of drugs and endogenous substrates such as triglycerides and diglycerides [114]. BTYNB is a small molecule compound found to have an inhibitory effect on IGF2BP1. BTYNB can selectively inhibit the binding of IGF2BP1 to its targets, thereby reducing the expression levels of its target mRNA and protein. BTYNB can effectively inhibit the proliferation of IGF2BP1-positive ovarian cancer and melanoma cells, while having no effect on IGF2BP1-negative cells [115]. CWI1-2 is a newly discovered small molecule compound found to inhibit IGF2BP2. Research has shown that by inhibiting IGF2BP2, CWI1-2 can regulate the expression of key targets (such as MYC, GPT2, and SLC1A5) in the glutamine metabolism pathway in an m6A-dependent manner, thereby inhibiting the development of AML and the self-renewal of leukemia stem cells [116]. JX5 is a small molecule compound with an inhibitory effect on IGF2BP2. JX5 inhibits the binding of IGF2BP2 to the oncogene NOTCH1 in T-ALL, thereby directly suppressing the proliferation of T-ALL in an m6A-dependent manner. Treatment with JX5 in T-ALL can produce effects similar to knocking out IGF2BP2, inhibiting the proliferation of T-ALL cells and prolonging animal survival [117]. These studies indicate that m6A reader inhibitors can effectively inhibit tumor progression, providing new potential treatment strategies for cancer patients. Currently, these new m6A reader drugs still face some challenges in clinical application, including issues such as drug bioavailability, toxicity, and side effects. Additionally, since m6A reader proteins also play important roles in normal cellular biological processes, inhibitors may have adverse effects on normal cell functions, leading to off-target effects and toxic reactions.
As of now, there have been no detailed research reports on small molecule inhibitors targeting YTHDC2. With further research on the mechanisms of action of YTHDC2 in cancer, there may be more studies on small molecule inhibitors targeting YTHDC2 in the future. These potential small molecule inhibitors may help explore the role of YTHDC2 in cancer development and provide new insights for the development of treatment strategies targeting YTHDC2.
Abbreviations
- m6A:
-
N6-methyladenosine
- MTC:
-
M6A methyltransferase complex
- METTL3:
-
Methyltransferase like 3
- METTL14:
-
Methyltransferase like 14
- WTAP:
-
Wilms tumor 1-associated protein
- RBM15:
-
RNA-binding motif protein 15
- SAM:
-
S-adenosylmethionine
- FTO:
-
Fat mass and obesity-related protein
- ALKBH5:
-
Alkylation repair homolog protein 5
- YTH:
-
YT521-B homology
- CLIP:
-
Crosslinking immunoprecipitation
- CDS:
-
Coding region
- SOX9:
-
Sex determining region Y-box 9
- LUAD:
-
Lung adenocarcinoma
- CYLD:
-
Cylindromatosis
- SLC7A11:
-
Solute carrier 7A11
- UTR:
-
Untranslated region
- HOXA13:
-
Homeobox A13
- SLC3A2:
-
Solid carrier 3A2
- MRPL12:
-
Mitochondrial ribosomal protein L12
- NSCLC:
-
Non-small cell lung cancer
- ID3:
-
Inhibitor of DNA-binding 3
- lncRNAs:
-
Long non-coding RNAs
- BTNL9:
-
Butyrophilin like 9
- eIF4GI:
-
Eukaryotic translation initiation factor 4 gamma 1
- VEGFA:
-
Vascular endothelial growth factor A
- GC:
-
Gastric cancer
- YAP:
-
Yes1 associated transcriptional regulator
- HCC:
-
Hepatocellular carcinoma
- ATG5:
-
Autophagy related 5
- PDAC:
-
Pancreatic ductal adenocarcinoma
- MLL1:
-
Lysine methyltransferase 2A
- CRC:
-
Colorectal cancer
- LIMK1:
-
LIM domain kinase 1
- 5-FU:
-
5-Fluorouracil
- miRNA:
-
MicroRNA
- MFN2:
-
Mitofusin 2
- HIF-1α:
-
Hypoxia-inducible factor-1 alpha
- PTC:
-
Papillary thyroid carcinoma
- PC:
-
Prostate cancer
- NPC:
-
Nasopharyngeal carcinoma
- cSCC:
-
Cutaneous squamous cell carcinoma
- SKCM:
-
Skin cutaneous melanoma
- OS:
-
Overall survival
- SNP:
-
Nucleotide polymorphism
- CRPC:
-
Castration-resistant prostate cancer
- CCNA2:
-
Cyclin A2
- FGCs:
-
Female germ cells
- NSCs:
-
Neural stem cells
- KSHV:
-
Kaposi’s sarcoma associated herpesvirus
- TM:
-
Talaromyces marneffei
- EAU:
-
Experimental autoimmune uveitis
- HCV:
-
Hepatitis C virus
- AMIGO2:
-
Adhesion molecule with Ig like domain 2
- DPN:
-
Diabetic peripheral neuropathy
- VSMCs:
-
Vascular smooth muscle cells
- NAFLD:
-
Non-alcoholic fatty liver disease
- CES2:
-
Carboxyesterase 2
- RUNX2:
-
RUNX family transcription factor 2
- BMSCs:
-
Bone marrow mesenchymal stem cells
- AML:
-
Acute myeloid leukemia
- T-ALL:
-
T-cell acute lymphoblastic leukemia
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Wu, X., Chen, H., Li, K. et al. The biological function of the N6-Methyladenosine reader YTHDC2 and its role in diseases. J Transl Med 22, 490 (2024). https://doi.org/10.1186/s12967-024-05293-6
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DOI: https://doi.org/10.1186/s12967-024-05293-6