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YTHDF2 regulates the adriamycin (ADM) resistance in NKTCL by modulating the m6A modification of SLC16A9
Meng Dong1, Xudong Zhang1, Zeyuan Wang1
1Department of Oncology, The First Affiliated Hospital of Zhengzhou University 450000, Zhengzhou, PR China.
Context:
Natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy with a high propensity for drug resistance, particularly to anthracyclines like adriamycin (ADM). The molecular mechanisms of ADM resistance in NKTCL are not fully understood.
Objective:
In this study, we aimed to elucidate the role of YTHDF2 in the regulation of SLC16A9 mRNA stability and its implications in ADM resistance in NKTCL.
Materials & Methods:
The study examined the expression changes of SLC16A9 under varying concentrations of ADM and manipulated the expression levels of SLC16A9 and YTHDF2 through overexpression and knockdown. By analyzing the levels of m6A modification, it was revealed that YTHDF2 regulates SLC16A9 expression via the m6A pathway, thereby influencing ADM resistance. This conclusion was further validated by in vivo experiments.
Results:
Our results showed that overexpression of SLC16A9 enhanced ADM resistance, while knockdown of SLC16A9 increased sensitivity to ADM. Further investigation revealed that ADM treatment reduces m6A modification levels on SLC16A9 mRNA, which is associated with decreased binding of YTHDF2 to SLC16A9 mRNA, leading to increased SLC16A9 expression. We also found that overexpression of YTHDF2 reduced SLC16A9 expression and increased ADM sensitivity, whereas knockdown of YTHDF2 had the opposite effect. In vivo experiments using a nude mouse model further confirmed that SLC16A9 knockdown reduces tumor growth and enhances sensitivity to ADM.
Conclusions:
our study provides direct evidence that YTHDF2 modulates ADM resistance in NKTCL by regulating the m6A modification of SLC16A9. Targeting the YTHDF2-m6A-SLC16A9 axis may offer a novel therapeutic strategy to overcome chemotherapy resistance in NKTCL.
Insights
Natural killer/T-cell lymphoma (NKTCL) drug resistance is linked to SLC16A9. The YTHDF2 protein regulates SLC16A9 via m6A modification, offering a new therapeutic target for overcoming adriamycin resistance in NKTCL.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Natural killer/T-cell lymphoma (NKTCL) is an aggressive cancer known for resistance to chemotherapy, particularly anthracyclines like adriamycin (ADM).
- The precise molecular mechanisms driving ADM resistance in NKTCL remain incompletely understood.
Purpose of the Study:
- To investigate the role of YTHDF2 in regulating SLC16A9 mRNA stability.
- To determine the implications of the YTHDF2-SLC16A9 interaction in ADM resistance within NKTCL.
Main Methods:
- Examined SLC16A9 expression changes in response to varying ADM concentrations.
- Manipulated SLC16A9 and YTHDF2 expression levels via overexpression and knockdown techniques.
- Analyzed m6A modification levels to confirm YTHDF2's regulation of SLC16A9 through the m6A pathway, validated by in vivo experiments.
Main Results:
- Overexpression of SLC16A9 increased ADM resistance, while its knockdown enhanced sensitivity.
- ADM treatment decreased m6A modification on SLC16A9 mRNA, reducing YTHDF2 binding and increasing SLC16A9 expression.
- YTHDF2 overexpression decreased SLC16A9 expression and boosted ADM sensitivity; YTHDF2 knockdown had opposing effects.
- In vivo studies confirmed that SLC16A9 knockdown reduced tumor growth and improved ADM sensitivity.
Conclusions:
- YTHDF2 directly modulates ADM resistance in NKTCL by controlling m6A modification of SLC16A9.
- The YTHDF2-m6A-SLC16A9 axis presents a potential novel therapeutic strategy to combat chemotherapy resistance in NKTCL.
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