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Original article
APOBEC3B interaction with PRC2 modulates microenvironment to promote HCC progression
  1. Duowei Wang1,
  2. Xianjing Li1,
  3. Jiani Li1,
  4. Yuan Lu1,
  5. Sen Zhao1,
  6. Xinying Tang1,
  7. Xin Chen1,
  8. Jiaying Li1,
  9. Yan Zheng1,
  10. Shuran Li1,
  11. Rui Sun1,
  12. Ming Yan1,
  13. Decai Yu2,
  14. Guangwen Cao3,
  15. Yong Yang1
  1. 1 Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
  2. 2 Department of General Surgery, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
  3. 3 Department of Epidemiology, Second Military Medical University, Shanghai, China
  1. Correspondence to Professor Yong Yang, Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210017, China; yy{at}


Objective APOBEC3B (A3B), a cytidine deaminase acting as a contributor to the APOBEC mutation pattern in many kinds of tumours, is upregulated in patients with hepatocellular carcinoma (HCC). However, APOBEC mutation patterns are absent in HCC. The mechanism of how A3B affects HCC progression remains elusive.

Design A3B ­promoter luciferase reporter and other techniques were applied to elucidate mechanisms of A3B upregulation in HCC. A3B overexpression and knockdown cell models, immunocompetent and immune-deficient mouse HCC model were conducted to investigate the influence of A3B on HCC progression. RNA­seq, flow cytometry and other techniques were conducted to analyse how A3B modulated the cytokine to enhance the recruitment of myeloid­-derived suppressor cells (MDSCs) and tumour­-associated macrophages (TAMs).

Results A3B upregulation through non-classical nuclear factor-κB (NF-κB)signalling promotes HCC growth in immunocompetent mice, associated with an increase of MDSCs, TAMs and programmed cell death1 (PD1) exprssed CD8+ T cells. A CCR2 antagonist suppressed TAMs and MDSCs infiltration and delayed tumour growth in A3B and A3BE68Q/E255Q­ expressing mouse tumours. Mechanistically, A3B upregulation in HCC depresses global H3K27me3 abundance via interaction with polycomb repressor complex 2 (PRC2) and reduces an occupancy of H3K27me3 on promoters of the chemokine CCL2 to recruit massive TAMs and MDSCs.

Conclusion Our observations uncover a deaminase-independent role of the A3B in modulating the HCC microenvironment and demonstrate a proof for the concept of targeting A3B in HCC immunotherapy.

  • cancer immunobiology
  • chemotaxis
  • hepatobiliary cancer
  • macrophages

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  • DW, XL, JL and YL contributed equally.

  • Contributors YY and DW conceived the project and designed the experiments. DW performed the study, analysed the data and wrote the paper. JN, YL, SZ, XC, JY, YZ, SR, RS and MY performed the study. DC and GW analysed the data. YY and XJ analysed the data and critically revised the manuscript. YY and DW are responsible for the overall content as guarantors. Obtained funding: YY.

  • Funding This work was supported by the National Natural Science Foundation of China (Nos 81673468, 91529304, 81473230, 81403020, 81273547, 81502407 and 81703562), the 111 Project (No 111-2-07), the Jiangsu Province Natural Science Foundation of China (Nos BK2014666 and BK20170732) and ’Double First-Class' University project (No CPU2018GF10 and CPU2018GY46).

  • Competing interests None declared.

  • Ethics approval The Affiliated Drum Tower Hospital.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This article has been corrected since it published Online First. The significance of this study box has been updated.

  • Patient consent for publication Obtained.

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