2. Academic Validation
  3. FTO-mediated DSP m6A demethylation promotes an aggressive subtype of growth hormone-secreting pituitary neuroendocrine tumors

FTO-mediated DSP m6A demethylation promotes an aggressive subtype of growth hormone-secreting pituitary neuroendocrine tumors

  • Mol Cancer. 2024 Sep 20;23(1):205. doi: 10.1186/s12943-024-02117-5.
Yunzhi Zou # 1,  Xiaoqiong Bao # 1,  Depei Li # 1,  Zhen Ye # 2,  Rong Xiang 1,  Yuanzhong Yang 1,  Zhe Zhu 3,  Ziming Chen 1,  Lingxing Zeng 1,  Chunling Xue 1,  Hongzhe Zhao 1,  Boyuan Yao 2,  Qilin Zhang 2,  Zeming Yan 1,  Zekun Deng 1,  Jintong Cheng 1,  Guanghao Yue 1,  Wanming Hu 1,  Jixiang Zhao 1,  Ruihong Bai 1,  Zhenhua Zhang 4,  Aiqun Liu 5,  Jialiang Zhang 6,  Zhixiang Zuo 7,  Xiaobing Jiang 8
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, China.
  • 3 Department of Pathology and Cell Biology, New York-Presbyterian Hospital, Columbia University Irving Medical Center, New York, NY, USA.
  • 4 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China.
  • 5 The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China. 179624095@qq.com.
  • 6 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.
  • 7 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.
  • 8 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.
  • # Contributed equally.
PMID: 39304899 DOI: 10.1186/s12943-024-02117-5
Abstract

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 N6-methyladenosine (m6A) in aggressive behavior has yet to be elucidated.

Methods: We performed m6A-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 m6A 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 m6A levels in SGGH compared to DGGH, with an elevated expression of fat mass and obesity-associated protein (FTO), an m6A 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 m6A demethylation destabilizes desmoplakin (DSP) mRNA, mediated by the m6A 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.

Keywords

Desmosome; Growth hormone-secreting pituitary neuroendocrine tumors; N6-methyladenosine; Pathological classification.

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