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Int J Cancer. 2019 Jul 1;145(1):164-178. doi: 10.1002/ijc.32065. Epub 2018 Dec 28.

The histone chaperone complex FACT promotes proliferative switch of G0 cancer cells.

Bi L1, Xie C2,3,4, Yao M3,4, Thae Hnit SS2, Vignarajan S3, Wang Y3,4, Wang Q5,6, Xi Z7,8, Xu H7,8, Li Z9, de Souza P10, Tee A11,12, Wong M11,12, Liu T11,12, Zhao X13, Zhou J1, Xu L1, Dong Q2,3,4.

Author information

1
Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2
School of Science and Health, Western Sydney University, Sydney, NSW, Australia.
3
Central Clinical School and Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia.
4
Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
5
Origins of Cancer Laboratory, Centenary Institute, Camperdown, NSW, Australia.
6
Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
7
School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
8
Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China.
9
Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
10
School of Medicine, Western Sydney University, Sydney, NSW, Australia.
11
Children's Cancer Institute Australia for Medical Research, Sydney, NSW, Australia.
12
Center for Childhood Cancer Research, UNSW Medicine, Sydney, NSW, Australia.
13
Shanghai Center for Systems Biology, Shanghai Jiao Tong University, Shanghai, China.

Abstract

Cancer cell repopulation through cell cycle re-entry by quiescent (G0 ) cell is thought to be an important mechanism behind treatment failure and cancer recurrence. Facilitates Chromatin Transcription (FACT) is involved in DNA repair, replication and transcription by eviction of histones or loosening their contact with DNA. While FACT expression is known to be high in a range of cancers, the biological significance of the aberrant increase is not clear. We found that in prostate and lung cancer cells FACT mRNA and protein levels were low at G0 compared to the proliferating state but replenished upon cell cycle re-entry. Silencing of FACT with Dox-inducible shRNA hindered cell cycle re-entry by G0 cancer cells, which could be rescued by ectopic expression of FACT. An increase in SKP2, c-MYC and PIRH2 and a decrease in p27 protein levels seen upon cell cycle re-entry were prevented or diminished when FACT was silenced. Further, using mVenus-p27K- infected cancer cells to measure p27 degradation capacity, we confirm that inhibition of FACT at release from quiescence suppressed the p27 degradation capacity resulting in an increased mVenus-p27K- signal. In conclusion, FACT plays an important role in promoting the transition from G0 to the proliferative state and can be a potential therapeutic target to prevent prostate and lung cancer from progression and recurrence.

KEYWORDS:

G0; MYC; SKP2; SPT16; SSRP1

PMID:
30548853
DOI:
10.1002/ijc.32065

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