ABSTRACT
Cell plasticity has been found to play a critical role in tumor progression and therapy resistance. However, our understanding of the characteristics and markers of plastic cellular states during cancer cell lineage transition remains limited. In this study, multi-omics analyses show that prostate cancer cells undergo an intermediate state marked by Zeb1 expression with epithelial-mesenchymal transition (EMT), stemness, and neuroendocrine features during the development of neuroendocrine prostate cancer (NEPC). Organoid-formation assays and in vivo lineage tracing experiments demonstrate that Zeb1+ epithelioid cells are putative cells of origin for NEPC. Mechanistically, Zeb1 transcriptionally regulates the expression of several key glycolytic enzymes, thereby predisposing tumor cells to utilize glycolysis for energy metabolism. During this process, lactate accumulation-mediated histone lactylation enhances chromatin accessibility and cellular plasticity including induction of neuro-gene expression, which promotes NEPC development. Collectively, Zeb1-driven metabolic rewiring enables the epigenetic reprogramming of prostate cancer cells to license the adeno-to-neuroendocrine lineage transition.
Subject(s)
Prostatic Neoplasms , Zinc Finger E-box-Binding Homeobox 1 , Male , Zinc Finger E-box-Binding Homeobox 1/metabolism , Zinc Finger E-box-Binding Homeobox 1/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Prostatic Neoplasms/genetics , Humans , Animals , Chromatin/metabolism , Epithelial-Mesenchymal Transition , Cell Line, Tumor , Mice , Gene Expression Regulation, Neoplastic , Neuroendocrine Tumors/metabolism , Neuroendocrine Tumors/pathology , Neuroendocrine Tumors/genetics , Cell Plasticity , Glycolysis , Chromatin Assembly and DisassemblyABSTRACT
Cadmium (Cd) hampers plant growth and harms photosynthesis. Glutamate (Glu) responds to Cd stress and activates the Ca2+ signaling pathway in duckweed, emphasizing Glu's significant role in Cd stress. In this study, we overexpressed phosphoserine aminotransferase (PSAT), a crucial enzyme in Glu metabolism, in duckweed. We investigated the response of PSAT-transgenic duckweed to Cd stress, including growth, Glu metabolism, photosynthesis, antioxidant enzyme activity, Cd2+ flux, and gene expression. Remarkably, under Cd stress, PSAT-transgenic duckweed prevented root abscission, upregulated the expression of photosynthesis ability, and increased Chl a, Chl b, and Chl a + b levels by 13.9%, 7%, and 12.6%, respectively. Antioxidant enzyme activity (CAT and SOD) also improved under Cd stress, reducing cell membrane damage in PSAT-transgenic duckweeds. Transcriptomic analysis revealed an upregulation of Glu metabolism-related enzymes in PSAT-transgenic duckweed under Cd stress. Moreover, metabolomic analysis showed a 68.4% increase in Glu content in PSAT duckweed exposed to Cd. This study sheds novel insights into the role of PSAT in enhancing plant resistance to Cd stress, establishing a theoretical basis for the impact of Glu metabolism on heavy metal tolerance in plants.
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.