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Chemical Modifiers in Cancer Treatment - Coggle Diagram
Chemical Modifiers in Cancer Treatment
How it works?
3 Proteins
Readers
-capable of decoding m6A methylation and generating a functional signal.
Eraser
-eraser is a fat mass and obesity-associated, selectively used to remove the methyl code from target mRNAs protein
Writer
-are used to catalyze the formation of m6A
Functions
Stability
-Knockout of METTL3 and METTL14 in embryonic stem cells can reduce mRNA decay, leading to increase of target mRNA expression, resistance of differentiation, enhancement of self-renewal and maintenance of the pluripotency state of embryonic stem cell.
Translation
-YTHDF1 is known to promote translation efficiency by binding with m6A. The translation efficiency decreases notably after YTHDF1 knockdown.YTHDF1 ensures the efficient protein production from m6A modification transcript.
Splicing and Export
-mRNA is spliced into mature transcript and exported from nucleus
-connects transcription with translation and mRNA export regulates gene expression.
Chemical modifier
Usage of agents that interacts chemically and physically with cytotoxic agents (radiation and chemotherapy)
modify the radiation interaction within target modules
Clinical relevance
Acute Myeloid Leukemia
• METTL3 and METTL14, two major components of m6A MTC, are important for selfrenewal of hemotopoietic stem cells (HSCs)
• METTL14 was critical for AML initiation and maintenance, as well as for the self-renewal of leukemia stem cells (LSCs) and drug response of AML cells, by regulating its important target transcript such as MYB and MYC.
Glioblastoma
• m6A RNA methylation is important for tumorigenesis, maintenance of self-renewal, and therapy resistence in GBM
• METTL3 and METTL14 funtion as tumor suppressors in GBM by regulating m6A modification and the mRNA level of target genes
HCC
• METTL14-dependent m6A methylation modulated the processing of primary miR126 to produce mature miR126 with a metastasis-suppressive function.
• METTL3 was shown to be significantly upregulated in HCC and associated with poor prognosis, and it played a critical oncogenic role in HCC by negatively regulating expression of SOCS2 through a YTHDF2-dependent mechanism
• YTHDF2 was specifically inhibited by the hypoxia environment of HCC, and its forced expression suppressed cell proliferation and tumor growth by destabilizing EGFR mRNA
• YTHDF1 was significantly upregulated in HCC and positively correlated with pathological stages and poor survival in HCC patient
Breast cancer
• Exposure of breast cancer cells to hypoxia, induced m6A hypomethylation and increased stabilization of NANOG and KLF4 mRNAs, which led to the enhanced breast cancer stem cell phenotype
Lung cancer
• METTL3 plays an oncogenic role in promoting lung cancer cell growth, survival, invasion, and transformation.
Advantages
RNA modification is reversible and dynamic
less toxic & fewer side effects compared to chemotherapy
RNA epigenetic modification can be combined with chemotherapy or immunotherapy
m6A machinery is deregulated in various human cancers and functions as oncogene or tumour suppressors
suggesting widespread interaction between m6A modification & human cancers
tightly controlled modification is important for hematopoietic homeostasis
Disadvantages
disregulation of m6A by aberrant experssion of either demethylase or methyltransferase
lead to differentiation blockage and leukemogenesis
METTL14 is critical for AML initiation and maintainance
as well as for self-renewal of leukemia stem cells (LSCs)
YTHF1 was significantly upregulated in HCC
positively correlated with pathological stages and poor survival in HCC patients
Currant challenges
restricted to a few of the most common modifications
the vast majority of RNA modifications remain hard to detect
functional study has been scarce
not adequate study on the function of writer and eraser genes depending on the cancer types
mechanism of different components of a given RNA modification machinery orchestrate the regulation of epitranscriptome in cancers have yet to be discovered