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

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. What's new? While solid tumors are known to enter periods of clinical dormancy, how cancer cells reside in this quiescent (G0) state and what circumstances cause them to re‐enter the cell cycle to facilitate cancer recurrence and progression remain unanswered. Here, G0 transition to a proliferative state in prostate and lung cancer cells was found to be dependent on the histone chaperone complex facilitates chromatin transcription (FACT). Experiments showed that FACT levels are reduced in G0 cancer cells and restored upon cell cycle re‐entry. Re‐entry was impeded by FACT silencing, which blocked p27 degradation, an event normally observed when cells resume proliferation.