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 2

ADORA2A promotes lineage plasticity and resistance to ADT in PCa cells.

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ADORA2A promotes lineage plasticity and resistance to ADT in PCa cells. ...
(A) Correlation analysis demonstrates a strong positive association between ADORA2A mRNA levels and NE-lineage gene signatures based on the Beltran PCa data set (24). (B) RT-qPCR results confirm ADORA2A-OE in LNCaP/AR-ADORA2A cells and suggest that NE-lineage associated genes are elevated in ADORA2A-OE LNCaP/AR cells compared with vector cells (n = 3). (C) Immunoblots of NE-lineage molecules and AR in ADORA2A-OE LNCaP/AR cells and vector control cells. (D) ADORA2A mRNA levels are negatively correlated with expression of AR signaling signature genes based on the analysis of the Beltran PCa data set (24). (E and F) RT-qPCR analysis of AR signature genes and stem cell marker genes in LNCaP/AR-vector and LNCaP/AR-ADORA2A cells (n = 3). (G) In vitro cell growth curves of LNCaP/AR-ADORA2A and LNCaP/AR-vector cells cultured in control medium or enzalutamide (ENZA, 15 μM)-containing medium (n = 5 biological replicates). (H and I) RT-qPCR (H) and immunoblotting (I) results demonstrate NE-lineage genes are decreased in response to the downregulation of ADORA2A in LASCPC-01 cells (n = 3). (J) Cell growth curves of LASCPC-01-scramble cells and LASCPC-01-shADORA2A cells within 6 days (n = 4 biological replicates). (K and L) Flow cytometry analysis (K) and quantification (L) of the apoptotic cells in LASCPC-01-scramble and LASCPC-01-shADORA2A cells (n = 3 biological replicates). For statistical analysis, student’s t test was used for B, E, and F; 1-way ANOVA with Dunnett’s posthoc test was utilized for H and L; 2-way ANOVA with Turkey’s posthoc test was applied in G and J. *P < 0.05, **P < 0.01, ***P < 0.001, data are presented as mean ± SEM. RT-qPCR and immunoblotting were repeated in at least 3 independent experiments, with similar results, and representative images are shown.