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Zeb1-controlled metabolic plasticity enables remodeling of chromatin accessibility in the development of neuroendocrine prostate cancer

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.

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Fig. 1: Zeb1 is dynamically expressed during the course of NEPC development.
Fig. 2: Single-cell sequencing data reveal dynamic changes of Zeb1 expression during human and mouse NEPC development.
Fig. 3: Zeb1+ epithelioid cells exhibit a more accessible chromatin with an expression characteristic of neuroactive and EMT program.
Fig. 4: Zeb1+ epithelioid cells can generate organoids with neuroendocrine characteristics.
Fig. 5: Lineage tracing indicates that Zeb1+ epithelioid cells are the cellular origin of NEPC.
Fig. 6: Zeb1 promotes glycolysis and accumulation of lactate in PCa.
Fig. 7: Lactate accumulation in Zeb1+ epithelioid cells enhances histone lactylation conferring lineage plasticity in PCa.

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Data availability

RNA-seq, ATAC-seq and CUT & Tag data in this study have been deposited to the National Genomics Data Center, China National Center for Bioinformation with Bioproject number PRJCA020095.

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Acknowledgements

The study was supported by funds from the National Key R&D Program of China (2022YFA1302704 and 2023YFC1404101), the National Natural Science Foundation of China U23A20454, NSFC82372873, NSFC32022021, and NSFC81872406, Shanghai Pilot Program for Basic Research-Shanghai Jiao Tong University (21TQ1400225), the Program of Shanghai Academic/Technology Research Leader (21XD1422300), the Shanghai Municipal Education Commission–Gaofeng Clinical Medicine Grant Support (20181706), the Innovative research team of high-level local universities in Shanghai, 111 project (B21024), Peak Disciplines (Type IV) of Institutions of Higher Learning in Shanghai, the KC Wong foundation.

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HHZ and WQG conceived the study; DW performed the experiments; GD, XC, JW, and NW supported data analysis; KL, NJ, YS, YL, and XX assisted in animal experiments; HZ and PX helped in construction of plasmids; YH and YZ participated in immunostaining and imaging; CC, WB, KZ, and PZ helped in experiments design. HHZ, WQG, and DW interpreted the data and wrote the manuscript.

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Correspondence to Wei-Qiang Gao or Helen He Zhu.

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Wang, D., Du, G., Chen, X. et al. Zeb1-controlled metabolic plasticity enables remodeling of chromatin accessibility in the development of neuroendocrine prostate cancer. Cell Death Differ 31, 779–791 (2024). https://doi.org/10.1038/s41418-024-01295-5

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