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Published on: November 5, 2014
NAT10-Mediated ac4C Modification of circANKRD12 Reprograms the Tumor Microenvironment
Jiale Zhang1,2, Hui Shi2, Chen Wang2
1Nanjing Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
Summary
N4-acetylcytidine (ac4C) modification of circANKRD12 by NAT10 generates a protein that drives multiple myeloma (MM) proliferation and suppresses immune cells. The drug desloratadine targets this axis, offering a new strategy for MM treatment.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Targeting both tumor growth and immune suppression is crucial for effective cancer therapy.
- The role of circular RNA (circRNA) chemical modifications in cancer, particularly multiple myeloma (MM), is not well understood.
Purpose of the Study:
- To investigate the role of N4-acetylcytidine (ac4C) modification in circANKRD12 and its impact on MM proliferation and immune evasion.
- To identify therapeutic strategies targeting the circANKRD12 pathway in MM.
Main Methods:
- Identified circANKRD12 as an ac4C substrate modified by NAT10 in MM.
- Characterized the translation of ac4C-modified circANKRD12 into circANKRD12_354aa.
- Investigated the interaction of circANKRD12_354aa with HDAC2 and its effect on c-Myc.
- Assessed the transfer of circANKRD12 to NK cells and its effect on cytotoxicity.
- Screened for drugs targeting circANKRD12_354aa and evaluated their efficacy in vivo.
Main Results:
- ac4C modification promotes circANKRD12 translation into circANKRD12_354aa, which stabilizes c-Myc, driving MM proliferation.
- circANKRD12 is transferred to NK cells, suppressing their cytotoxicity via the HDAC2/c-Myc pathway and promoting immune evasion.
- circANKRD12 is upregulated in MM patients and associated with poor prognosis.
- Desloratadine was identified as a direct binder of circANKRD12_354aa and effectively suppressed MM growth and restored NK cell immunity in vivo.
Conclusions:
- NAT10-mediated ac4C modification of circANKRD12 is a key mechanism coordinating MM cell proliferation and immune dysfunction.
- circANKRD12_354aa is a promising therapeutic target for MM, and desloratadine shows potential for restoring antitumor immunity.
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