ADORA2A-driven proline synthesis triggers epigenetic reprogramming in neuroendocrine prostate and lung cancers
Na Jing, … , Wei-Qiang Gao, Helen He Zhu
Na Jing, … , Wei-Qiang Gao, Helen He Zhu
Published December 15, 2023
Citation Information: J Clin Invest. 2023;133(24):e168670. https://doi.org/10.1172/JCI168670.
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Research Article Metabolism Oncology

ADORA2A-driven proline synthesis triggers epigenetic reprogramming in neuroendocrine prostate and lung cancers

Abstract

Cell lineage plasticity is one of the major causes for the failure of targeted therapies in various cancers. However, the driver and actionable drug targets in promoting cancer cell lineage plasticity are scarcely identified. Here, we found that a G protein-coupled receptor, ADORA2A, is specifically upregulated during neuroendocrine differentiation, a common form of lineage plasticity in prostate cancer and lung cancer following targeted therapies. Activation of the ADORA2A signaling rewires the proline metabolism via an ERK/MYC/PYCR cascade. Increased proline synthesis promotes deacetylases SIRT6/7-mediated deacetylation of histone H3 at lysine 27 (H3K27), and thereby biases a global transcriptional output toward a neuroendocrine lineage profile. Ablation of Adora2a in genetically engineered mouse models inhibits the development and progression of neuroendocrine prostate and lung cancers, and, intriguingly, prevents the adenocarcinoma-to-neuroendocrine phenotypic transition. Importantly, pharmacological blockade of ADORA2A profoundly represses neuroendocrine prostate and lung cancer growth in vivo. Therefore, we believe that ADORA2A can be used as a promising therapeutic target to govern the epigenetic reprogramming in neuroendocrine malignancies.

Authors

Na Jing, Kai Zhang, Xinyu Chen, Kaiyuan Liu, Jinming Wang, Lingling Xiao, Wentian Zhang, Pengfei Ma, Penghui Xu, Chaping Cheng, Deng Wang, Huifang Zhao, Yuman He, Zhongzhong Ji, Zhixiang Xin, Yujiao Sun, Yingchao Zhang, Wei Bao, Yiming Gong, Liancheng Fan, Yiyi Ji, Guanglei Zhuang, Qi Wang, Baijun Dong, Pengcheng Zhang, Wei Xue, Wei-Qiang Gao, Helen He Zhu

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Figure 8

Deletion of Adora2a suppresses the tumor development in a NE lung cancer model.

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Deletion of Adora2a suppresses the tumor development in a NE lung cancer...
(A) A schematic showing the method of generation of a NE lung cancer model. Briefly, the Cre-expressing adenovirus (Adeno-Cre) were intratracheally injected into the Rb1fl/fl; Trp53fl/fl and Rb1fl/fl; Trp53fl/fl; Adora2afl/fl mice to establish the Adeno-DKO and Adeno-TKO lung cancer mouse models. (B) Body weight of Adeno-DKO (n = 8) and Adeno-TKO (n = 8) mice at early stage of 90 days after Adeno-Cre injection. (C) The H&E staining displays overall tumor formation of Adeno-DKO and Adeno-TKO mice in the lung at early stage; scale bar: 1 mm; zoom image scale bar: 50 μm. IHC images demonstrate the expression of SYP and Ki67 in the lung tumor of Adeno-DKO and Adeno-TKO mice, scale bar = 100 μm; zoom image scale bar: 30 μm. (D) The lung tissues of Adeno-DKO and Adeno-TKO mice at late stage of 240 days after Adeno-Cre administration are shown. Dotted red lines indicate the tumor area on the lung tissue. Scale bar: 2mm. (E) Quantification of lung tumor lesions with distinct diameters in Adeno-DKO (n = 4) and Adeno-TKO (n = 3) mice at late stage of 240 days after Adeno-Cre injection. (F) H&E images exhibit tumor formations in the lung of Adeno-DKO and Adeno-TKO mice at late stage of 240 days after Adeno-Cre injection. Scale bar: 1 mm. For statistical analysis, student’s t test was used for B. **P < 0.01, data are presented as mean ± SEM.