RT Journal Article
SR Electronic
T1 Histone chaperone FACT complex mediates oxidative stress response to promote liver cancer progression
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 329
OP 342
DO 10.1136/gutjnl-2019-318668
VO 69
IS 2
A1 Jialing Shen
A1 Mengnuo Chen
A1 Derek Lee
A1 Cheuk-Ting Law
A1 Lai Wei
A1 Felice Ho-Ching Tsang
A1 Don Wai-Ching Chin
A1 Carol Lai-Hung Cheng
A1 Joyce Man-Fong Lee
A1 Irene Oi-Lin Ng
A1 Carmen Chak-Lui Wong
A1 Chun-Ming Wong
YR 2020
UL http://gut.bmj.com/content/69/2/329.abstract
AB 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.