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.

Correctly identifying the cells of origin is essential for tailoring treatment and understanding the emergence of cancer stem cells and late metastases

“…Lung NE cells are the source of the presently called NETs, previously carcinoids ( 43 ), whereas the cell of origin of the small and large cell pulmonary carcinomas remains unknown and is not clarified since the early stages of these tumors have not been identified ( 44 ). Finally, trans-differentiation may be an alternative for NE cells as the cell of origin for lung NE cancers as well as cancers of the prostate ( 45 ).…”

Chromatin modifiers in human disease: from functional roles to regulatory mechanisms

“…For example, crosstalk between histone-modifying enzymes and enhancers promotes the activation of proto-oncogenes, causing tumors such as liver, breast, and colorectal cancers [89][90][91][92]. The G protein-coupled receptor A2A activates the proto-oncogene MYC to promote proline synthesis, and the increased level of proline metabolism recruits histone acetylases SIRT6 and SIRT7 to mediate the level of H3 deacetylation in prostate cancer cells, triggering the transformation of prostate adenocarcinoma into a neuroendocrine tumor [93]. Similarly, P300 synergizes with BRD4 (transcriptional cofactor) to promote the activation of the proto-oncogene MYC in aggressive squamous cell carcinoma [94].…”