Enhancing circadian clock function in cancer cells inhibits tumor growth

Abstract

BackgroundCircadian clocks control cell cycle factors, and circadian disruption promotes cancer. To address whether enhancing circadian rhythmicity in tumor cells affects cell cycle progression and reduces proliferation, we compared growth and cell cycle events of B16 melanoma cells and tumors with either a functional or dysfunctional clock.ResultsWe found that clock genes were suppressed in B16 cells and tumors, but treatments inducing circadian rhythmicity, such as dexamethasone, forskolin and heat shock, triggered rhythmic clock and cell cycle gene expression, which resulted in fewer cells in S phase and more in G1 phase. Accordingly, B16 proliferation in vitro and tumor growth in vivo was slowed down. Similar effects were observed in human colon carcinoma HCT-116 cells. Notably, the effects of dexamethasone were not due to an increase in apoptosis nor to an enhancement of immune cell recruitment to the tumor. Knocking down the essential clock gene Bmal1 in B16 tumors prevented the effects of dexamethasone on tumor growth and cell cycle events.ConclusionsHere we demonstrated that the effects of dexamethasone on cell cycle and tumor growth are mediated by the tumor-intrinsic circadian clock. Thus, our work reveals that enhancing circadian clock function might represent a novel strategy to control cancer progression.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-017-0349-7) contains supplementary material, which is available to authorized users.

The tumor circadian clock: a new target for cancer therapy?

“…This was not due to an effect on the host-immune response, and moreover, inhibition of the tumor clock by shRNA-mediated knockdown completely prevented the effects of DEX, implying that they were happening via the tumor clock. Similar results were found in another cancer cell-type, the human colon carcinoma HCT-116 cells, pointing to the broader applicability of the concept [22].…”

“…Since the cell cycle is under circadian control, cancer cells might enhance their proliferation through manipulation of the circadian control over the cell cycle. Notably, our evidence indicates that the reduced proliferation and tumor growth due to activation of the tumor clock is achieved by inducing oscillations of cell-cycle genes important for the G1-to-S transition, such as c-Myc, Cyclin E and p21, which subsequently decreases the entry in S phase [22]. Taken together, current literature supports the strategy of acting on the tumor clock in order to control tumor progression.…”

“…When used to generate subcutaneous solid tumors in mice, the B16 cells did not show clock gene rhythms in vivo unless they were injected with DEX. This treatment both restored clock function and dramatically slowed down tumor growth (about two-third reduction after only 1 week) [22]. This was not due to an effect on the host-immune response, and moreover, inhibition of the tumor clock by shRNA-mediated knockdown completely prevented the effects of DEX, implying that they were happening via the tumor clock.…”

“…Instead of inactivating the tumor clock, we reasoned that since most cancer cell lines and various tumor tissues harbor a dysfunctional circadian clock, then rescuing the circadian clock in tumor cells might inhibit or slow down their growth [22]. We found suppressed clock gene expression in B16 mouse melanoma cells, and were able to restore rhythmic clock gene expression by various treatments such as dexamethasone (DEX), forskolin or heat shock.…”

Histone deacetylase inhibitors induce the expression of tumor suppressor genes Per1 and Per2 in human gastric cancer cells

“…The maintenance of the molecular mechanism of the circadian clockwork has a profound influence on human health, and its alteration has frequently been associated with multiple diseases, including cancer (7)(8)(9)(10)(11)(12). Several in vivo and in vitro studies suggest that, in addition to their main role within the molecular mechanism of the circadian clock, Period circadian regulator (Per)1 and Per2 genes can also function as tumor suppressors due to their involvement in cell proliferation, apoptosis, cell cycle control, and DNA damage response (13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”