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Histone chaperone FACT complex mediates oxidative stress response to promote liver cancer progression
  1. Jialing Shen1,2,
  2. Mengnuo Chen1,2,
  3. Derek Lee1,2,
  4. Cheuk-Ting Law1,2,
  5. Lai Wei1,2,
  6. Felice Ho-Ching Tsang1,2,
  7. Don Wai-Ching Chin1,2,
  8. Carol Lai-Hung Cheng1,2,
  9. Joyce Man-Fong Lee1,2,
  10. Irene Oi-Lin Ng1,2,
  11. Carmen Chak-Lui Wong1,2,
  12. Chun-Ming Wong1,2
  1. 1State Key Laboratory of Liver Research, University of Hong Kong, Hong Kong, Hong Kong
  2. 2Department of Pathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Hong Kong
  1. Correspondence to Dr Chun-Ming Wong, State Key Laboratory of Liver Research and Department of Pathology, University of Hong Kong Li Ka Shing, Hong Kong, Hong Kong; jackwong{at}pathology.hku.hk; Dr Carmen Chak-Lui Wong, Department of Pathology, The University of Hong Kong, Hong Kong, China; carmencl{at}pathology.hku.hk

Abstract

Objective Facilitates Chromatin Transcription (FACT) complex is a histone chaperone participating in DNA repair-related and transcription-related chromatin dynamics. In this study, we investigated its oncogenic functions, underlying mechanisms and therapeutic implications in human hepatocellular carcinoma (HCC).

Design We obtained HCC and its corresponding non-tumorous liver samples from 16 patients and identified FACT complex as the most upregulated histone chaperone by RNA-Seq. We further used CRISPR-based gene activation and knockout systems to demonstrate the functions of FACT complex in HCC growth and metastasis. Functional roles and mechanistic insights of FACT complex in oxidative stress response were investigated by ChIP assay, flow cytometry, gene expression assays and 4sU-DRB transcription elongation assay. Therapeutic effect of FACT complex inhibitor, Curaxin, was tested in both in vitro and in vivo models.

Results We showed that FACT complex was remarkably upregulated in HCC and contributed to HCC progression. Importantly, we unprecedentedly revealed an indispensable role of FACT complex in NRF2-driven oxidative stress response. Oxidative stress prevented NRF2 and FACT complex from KEAP1-mediated protein ubiquitination and degradation. Stabilised NRF2 and FACT complex form a positive feedback loop; NRF2 transcriptionally activates the FACT complex, while FACT complex promotes the transcription elongation of NRF2 and its downstream antioxidant genes through facilitating rapid nucleosome disassembly for the passage of RNA polymerase. Therapeutically, Curaxin effectively suppressed HCC growth and sensitised HCC cell to sorafenib.

Conclusion In conclusion, our findings demonstrated that FACT complex is essential for the expeditious HCC oxidative stress response and is a potential therapeutic target for HCC treatment.

  • hepatocellular carcinoma
  • SUPT16H
  • SSRP1
  • FACT complex
  • ROS
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Footnotes

  • Contributors Conceptualisation: JS, CC-LW, CMW. Methodology: JS, C-TL, CC-LW, CMW. Formal analysis: JS, C-TL, CMW. Investigation: JS, MC, DL, LW, FH-CT, DC-WC, CL-HC, JL, CC-LW, CMW. Resource: IOLN, CC-LW, CMW. Funding acquisition: IOLN, CC-LW, CMW. Writing original draft: JS, CC-LW, CMW. Writing—review and editing: JS, CC-LW, CMW. Supervision: CC-LW, CMW.

  • Funding This study was funded by RGC-TBRS 2016 (T12-704/16-R), Health and Medical Research Fund 2018 (05161786).

  • Competing interests None declared.

  • Patient consent for publication Not required.

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

  • Data availability statement All data relevant to the study are included in the article or uploaded as online supplementary information.

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