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.
View: Text | PDF
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

×

Figure 3

ADORA2A signaling promotes the proline synthesis by upregulating PYCRs.

Options: View larger image (or click on image) Download as PowerPoint
ADORA2A signaling promotes the proline synthesis by upregulating PYCRs. ...
(A) GSEA analysis reveals upregulated biological processes and pathways in KEGG enrichment analysis in LNCaP/AR-ADORA2A versus LNCaP/AR-vector cells (n = 3 biological replicates per cell line). (B) The GSEA plot shows that arginine and proline metabolism-related genes are enriched in NEPC compared with ADPC based on analysis of the Beltran PCa data set (24). (C) Mass spectrometry assesses the intracellular amount of proline and arginine in LNCaP/AR-vector and LNCaP/AR-ADORA2A cells in the absence or in the presence of ADORA2A agonist CGS (100 nM, treated for 48 hours) or antagonist SCH58261 (25 μM, treated for 48 hours) (n = 3 biological replicates/group). (D) The schematic flowchart displays the proline synthesis and key enzymes. (E and F) RT-qPCR (E) and immunoblotting (F) assays reveal the expression levels of PYCR1, PYCR2, and PYCR3 in response to ectopic expression of ADORA2A in LNCaP/AR cells (n = 3). (G) RT-qPCR data demonstrate decreases of PYCR1 and PYCR2 transcription upon the downregulation of ADORA2A via shRNA in LASCPC-01 cells (n = 3). (H) Immunoblotting results display reduced PYCR1 and PYCR2 at the protein level in response to ADORA2A knockdown in LASCPC-01 cells. For statistical analysis, 1-way ANOVA with Turkey’s posthoc test and Kruskal-Wallis test with Dunnett’s posthoc test was utilized for C; student’s t test was used for E; 1-way ANOVA with Dunnett’s posthoc test was applied in G.**P < 0.01, ***P < 0.001, data are presented as mean ± SEM. RT-qPCR and immunoblotting were repeated in 3 independent experiments, with similar results, and representative images are shown.