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Gut. 2019 Aug 22. pii: gutjnl-2019-318668. doi: 10.1136/gutjnl-2019-318668. [Epub ahead of print]

Histone chaperone FACT complex mediates oxidative stress response to promote liver cancer progression.

Shen J1,2, Chen M1,2, Lee D1,2, Law CT1,2, Wei L1,2, Tsang FH1,2, Chin DW1,2, Cheng CL1,2, Lee JM1,2, Ng IO1,2, Wong CC3,2, Wong CM3,2.

Author information

1
State Key Laboratory of Liver Research, University of Hong Kong, Hong Kong, Hong Kong.
2
Department of Pathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Hong Kong.
3
State Key Laboratory of Liver Research, University of Hong Kong, Hong Kong, Hong Kong jackwong@pathology.hku.hk carmencl@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.

KEYWORDS:

FACT complex; ROS; SSRP1; SUPT16H; hepatocellular carcinoma

PMID:
31439637
DOI:
10.1136/gutjnl-2019-318668

Conflict of interest statement

Competing interests: None declared.

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