دورية أكاديمية
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KAP1 stabilizes MYCN mRNA and promotes neuroblastoma tumorigenicity by protecting the RNA m 6 A reader YTHDC1 protein degradation.

التفاصيل البيبلوغرافية
العنوان: KAP1 stabilizes MYCN mRNA and promotes neuroblastoma tumorigenicity by protecting the RNA m 6 A reader YTHDC1 protein degradation.
المؤلفون: Yang Y; Pediatric Translational Medicine Institute, Department of Hematology & Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai, 200127, China., Zhang Y; State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China., Chen G; State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China., Sun B; State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China., Luo F; State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China., Gao Y; Pediatric Translational Medicine Institute, Department of Hematology & Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai, 200127, China., Feng H; State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. fenghaizhong@sjtu.edu.cn., Li Y; Pediatric Translational Medicine Institute, Department of Hematology & Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai, 200127, China. liyanxin@scmc.com.cn.
المصدر: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2024 May 14; Vol. 43 (1), pp. 141. Date of Electronic Publication: 2024 May 14.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: BioMed Central Country of Publication: England NLM ID: 8308647 Publication Model: Electronic Cited Medium: Internet ISSN: 1756-9966 (Electronic) Linking ISSN: 03929078 NLM ISO Abbreviation: J Exp Clin Cancer Res Subsets: MEDLINE
أسماء مطبوعة: Publication: 2009- : London : BioMed Central
Original Publication: [Roma] : APSIT,
مواضيع طبية MeSH: N-Myc Proto-Oncogene Protein*/genetics , N-Myc Proto-Oncogene Protein*/metabolism , Neuroblastoma*/genetics , Neuroblastoma*/metabolism , Neuroblastoma*/pathology , Tripartite Motif-Containing Protein 28*/metabolism , Tripartite Motif-Containing Protein 28*/genetics, Animals ; Humans ; Mice ; Adenosine/analogs & derivatives ; Adenosine/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Mice, Nude ; RNA Splicing Factors/metabolism ; RNA Splicing Factors/genetics ; RNA Stability ; RNA, Messenger/genetics ; RNA, Messenger/metabolism
مستخلص: Background: Neuroblastoma (NB) patients with amplified MYCN often face a grim prognosis and are resistant to existing therapies, yet MYCN protein is considered undruggable. KAP1 (also named TRIM28) plays a crucial role in multiple biological activities. This study aimed to investigate the relationship between KAP1 and MYCN in NB.
Methods: Transcriptome analyses and luciferase reporter assay identified that KAP1 was a downstream target of MYCN. The effects of KAP1 on cancer cell proliferation and colony formation were explored using the loss-of-function assays in vitro and in vivo. RNA stability detection was used to examine the influence of KAP1 on MYCN expression. The mechanisms of KAP1 to maintain MYCN mRNA stabilization were mainly investigated by mass spectrum, immunoprecipitation, RIP-qPCR, and western blotting. In addition, a xenograft mouse model was used to reveal the antitumor effect of STM2457 on NB.
Results: Here we identified KAP1 as a critical regulator of MYCN mRNA stability by protecting the RNA N 6 -methyladenosine (m 6 A) reader YTHDC1 protein degradation. KAP1 was highly expressed in clinical MYCN-amplified NB and was upregulated by MYCN. Reciprocally, KAP1 knockdown reduced MYCN mRNA stability and inhibited MYCN-amplified NB progression. Mechanistically, KAP1 regulated the stability of MYCN mRNA in an m 6 A-dependent manner. KAP1 formed a complex with YTHDC1 and RNA m 6 A writer METTL3 to regulate m 6 A-modified MYCN mRNA stability. KAP1 depletion decreased YTHDC1 protein stability and promoted MYCN mRNA degradation. Inhibiting MYCN mRNA m 6 A modification synergized with chemotherapy to restrain tumor progression in MYCN-amplified NB.
Conclusions: Our research demonstrates that KAP1, transcriptionally activated by MYCN, forms a complex with YTHDC1 and METTL3, which in turn maintain the stabilization of MYCN mRNA in an m 6 A-dependent manner. Targeting m 6 A modification by STM2457, a small-molecule inhibitor of METTL3, could downregulate MYCN expression and attenuate tumor proliferation. This finding provides a new alternative putative therapeutic strategy for MYCN-amplified NB.
(© 2024. The Author(s).)
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معلومات مُعتمدة: 32271007 National Natural Science Foundation of China; 820728968,32371004 National Natural Science Foundation of China; 23ZR1441000 Shanghai Natural Science Foundation; 21XD1403100 Program of Shanghai Academic/Technology Research Leader
فهرسة مساهمة: Keywords: KAP1; METTL3; MYCN; Neuroblastoma; YTHDC1; m6A; mRNA stability
المشرفين على المادة: K72T3FS567 (Adenosine)
0 (N-Myc Proto-Oncogene Protein)
0 (RNA Splicing Factors)
0 (RNA, Messenger)
EC 2.3.2.27 (Tripartite Motif-Containing Protein 28)
EC 2.3.2.27 (TRIM28 protein, human)
0 (MYCN protein, human)
0 (YTHDC1 protein, human)
تواريخ الأحداث: Date Created: 20240514 Date Completed: 20240515 Latest Revision: 20240717
رمز التحديث: 20240717
مُعرف محوري في PubMed: PMC11092262
DOI: 10.1186/s13046-024-03040-9
PMID: 38745192
قاعدة البيانات: MEDLINE
الوصف
تدمد:1756-9966
DOI:10.1186/s13046-024-03040-9