ADORA2A-driven proline synthesis triggers epigenetic reprogramming in neuroendocrine prostate and lung cancers
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
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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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 9

Pharmacological inhibition of ADORA2A restrains NE tumor growth in vitro and in vivo.

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Pharmacological inhibition of ADORA2A restrains NE tumor growth in vitro...
(A and B) The Cell Titer Glo assay shows that the ADORA2A antagonist SCH58261 restrains the proliferation of LASCPC-01 (A) and LNCaP/AR-shRB1/TP53 (B) NEPC cells in vitro (n = 4 biological replicates/group). (C and D) SCH58261 exerts no inhibitory effect on the proliferation of VCaP (C) cells and LNCaP/AR (D) ADPC cells in vitro (n = 4 biological replicates/group). (E and F) The in vivo tumor growth curves (E) and the endpoint tumors (F) derived from TRAMP-C1 (TC1) cells that were treated with either vehicle and SCH58261 (vehicle, n = 10; SCH58261, n = 6; Cells were subcutaneously injected into 6-week-old male BALB/c nude hosts). (G and H) The in vivo tumor growth curves (G) and the endpoint tumors (H) derived from Myc-CaP cells that were treated with either vehicle and SCH58261 (vehicle, n = 14; SCH58261, n = 14; Cells were s.c. inoculated into 6-week-old male FVB hosts). (I and J) The in vivo tumor growth curves (I) and the endpoint tumors (J) derived from LASCPC-01 cells that were treated with either vehicle and SCH58261 (vehicle, n = 13; SCH58261, n = 13; cells were s.c. injected into 6-week-old male BALB/c nude mice). (K and L) The in vivo tumor growth curves (I) and the endpoint tumors (J) derived from NCI-H146 cells that were treated with either vehicle and SCH58261 (vehicle, n = 5; SCH58261, n = 7; cells were s.c. injected into 6-week-old male BALB/c nude hosts). Student’s t test was used in A–D, E, G, I, and K. *P < 0.05, **P < 0.01. The SCH58261 powder was dissolved in 3% DMSO, 10% HS-15, and 87% saline solution. 3 mg/kg SCH58261 was i.p. administered to each mouse every other day.