دورية أكاديمية
أعرض في EDS

FTO-mediated DSP m 6 A demethylation promotes an aggressive subtype of growth hormone-secreting pituitary neuroendocrine tumors.

التفاصيل البيبلوغرافية
العنوان: FTO-mediated DSP m 6 A demethylation promotes an aggressive subtype of growth hormone-secreting pituitary neuroendocrine tumors.
المؤلفون: Zou Y; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China., Bao X; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China., Li D; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China., Ye Z; Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, China., Xiang R; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China., Yang Y; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China., Zhu Z; Department of Pathology and Cell Biology, New York-Presbyterian Hospital, Columbia University Irving Medical Center, New York, NY, USA., Chen Z; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China., Zeng L; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China., Xue C; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China., Zhao H; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China., Yao B; Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, China., Zhang Q; Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, China., Yan Z; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China., Deng Z; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China., Cheng J; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China., Yue G; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China., Hu W; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China., Zhao J; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China., Bai R; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China., Zhang Z; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China., Liu A; The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China. 179624095@qq.com., Zhang J; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China. zhangjial@sysucc.org.cn., Zuo Z; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China. zuozhx@sysucc.org.cn., Jiang X; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China. jiangxiaob1@sysucc.org.cn.
المصدر: Molecular cancer [Mol Cancer] 2024 Sep 20; Vol. 23 (1), pp. 205. Date of Electronic Publication: 2024 Sep 20.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: BioMed Central Country of Publication: England NLM ID: 101147698 Publication Model: Electronic Cited Medium: Internet ISSN: 1476-4598 (Electronic) Linking ISSN: 14764598 NLM ISO Abbreviation: Mol Cancer Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : BioMed Central, c2002-
مواضيع طبية MeSH: Alpha-Ketoglutarate-Dependent Dioxygenase FTO*/metabolism , Alpha-Ketoglutarate-Dependent Dioxygenase FTO*/genetics , Neuroendocrine Tumors*/metabolism , Neuroendocrine Tumors*/genetics , Neuroendocrine Tumors*/pathology , Demethylation*, Humans ; Animals ; Mice ; Adenosine/analogs & derivatives ; Adenosine/metabolism ; Pituitary Neoplasms/metabolism ; Pituitary Neoplasms/genetics ; Pituitary Neoplasms/pathology ; Gene Expression Regulation, Neoplastic ; Cell Line, Tumor ; Female ; Male ; Growth Hormone-Secreting Pituitary Adenoma/metabolism ; Growth Hormone-Secreting Pituitary Adenoma/genetics ; Growth Hormone-Secreting Pituitary Adenoma/pathology
مستخلص: Background: Growth hormone-secreting pituitary neuroendocrine tumors can be pathologically classified into densely granulated (DGGH) and sparsely granulated types (SGGH). SGGH is more aggressive and associated with a poorer prognosis. While epigenetic regulation is vital in tumorigenesis and progression, the role of N 6 -methyladenosine (m 6 A) in aggressive behavior has yet to be elucidated.
Methods: We performed m 6 A-sequencing on tumor samples from 8 DGGH and 8 SGGH patients, complemented by a suite of assays including ELISA, immuno-histochemistry, -blotting and -fluorescence, qPCR, MeRIP, RIP, and RNA stability experiments, aiming to delineate the influence of m 6 A on tumor behavior. We further assessed the therapeutic potential of targeted drugs using cell cultures, organoid models, and animal studies.
Results: We discovered a significant reduction of m 6 A levels in SGGH compared to DGGH, with an elevated expression of fat mass and obesity-associated protein (FTO), an m 6 A demethylase, in SGGH subtype. Series of in vivo and in vitro experiments demonstrated that FTO inhibition in tumor cells robustly diminishes hypoxia resistance, attenuates growth hormone secretion, and augments responsiveness to octreotide. Mechanically, FTO-mediated m 6 A demethylation destabilizes desmoplakin (DSP) mRNA, mediated by the m 6 A reader FMR1, leading to prohibited desmosome integrity and enhanced tumor hypoxia tolerance. Targeting the FTO-DSP-SSTR2 axis curtailed growth hormone secretion, therefor sensitizing tumors to octreotide therapy.
Conclusion: Our study reveals the critical role of FTO in the aggressive growth hormone-secreting pituitary neuroendocrine tumors subtype and suggests FTO may represent a new therapeutic target for refractory/persistent SGGH.
(© 2024. The Author(s).)
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معلومات مُعتمدة: YTP-SYSUCC-0062 Young Talents Program of Sun Yat-sen University Cancer Center; 2021B1515020108 Guangdong Basic and Applied Basic Research Foundation; 2022A1515012430 Guangdong Basic and Applied Basic Research Foundation; M202206 Guangdong Esophageal Cancer Institute Science and Technology Program; 82372624 National Natural Science Foundation of China; 2024A1515013102 Basic and Applied Basic Research Foundation of Guangdong Province
فهرسة مساهمة: Keywords: Desmosome; Growth hormone-secreting pituitary neuroendocrine tumors; N6-methyladenosine; Pathological classification
المشرفين على المادة: EC 1.14.11.33 (Alpha-Ketoglutarate-Dependent Dioxygenase FTO)
EC 1.14.11.33 (FTO protein, human)
CLE6G00625 (N-methyladenosine)
K72T3FS567 (Adenosine)
تواريخ الأحداث: Date Created: 20240920 Date Completed: 20240921 Latest Revision: 20240923
رمز التحديث: 20240923
مُعرف محوري في PubMed: PMC11414129
DOI: 10.1186/s12943-024-02117-5
PMID: 39304899
قاعدة البيانات: MEDLINE
الوصف
تدمد:1476-4598
DOI:10.1186/s12943-024-02117-5