Abstract
Circadian clock dysregulation promotes cancer growth. Here we show that PFKFB3, the gene that encodes for inducible 6-phosphofructo-2-kinase as an essential supporting enzyme of cancer cell survival through stimulating glycolysis, mediates circadian control of carcinogenesis. In patients with tongue cancers, PFKFB3 expression in both cancers and its surrounding tissues was increased significantly compared with that in the control, and was accompanied with dys-regulated expression of core circadian genes. In the in vitro systems, SCC9 tongue cancer cells displayed rhythmic expression of PFKFB3 and CLOCK that was distinct from control KC cells. Furthermore, PFKFB3 expression in SCC9 cells was stimulated by CLOCK through binding and enhancing the transcription activity of PFKFB3 promoter. Inhibition of PFKFB3 at zeitgeber time 7 (ZT7), but not at ZT19 caused significant decreases in lactate production and in cell proliferation. Consistently, PFKFB3 inhibition in mice at circadian time (CT) 7, but not CT19 significantly reduced the growth of implanted neoplasms. Taken together, these findings demonstrate PFKFB3 as a mediator of circadian control of cancer growth, thereby highlighting the importance of time-based PFKFB3 inhibition in cancer treatment.
Highlights
Circadian clocks drive daily rhythms and coordinate many bio-physiological processes of living organisms to match environmental light-dark cycles[1,2]
The mRNA levels of PFKFB3, along with several core clock genes were analyzed. Compared with those in normal epithelium, the mRNA levels of PFKFB3 were increased in both cancer tissues and its surrounding tissues, which were accompanied with significant decreases in the mRNA levels of BMAL1 and CLOCK in the same tissues (Fig. 1B)
The expression of key clock genes whose products generate feedback inhibitory effects on BMAL1/CLOCK transcription activity in cancer tissues and its surrounding tissues was distinct from that in normal tissues. These genes include Period[1] (PER1), PER2, and PER3, as well as Cryptochrome 1 (CRY1) and CRY2 (Fig. 1B). These results suggest that PFKFB3 expression is increased and associated with the dysregulation of core clock gene expression in human tongue cancer
Summary
Circadian clocks drive daily rhythms and coordinate many bio-physiological processes of living organisms to match environmental light-dark cycles[1,2]. The link between circadian clock dysregulation and cancer development and progression implies the feasibility of timed anti-cancer therapies in order to generate maximal therapeutic effects and minimal unwanted-side effects[19,20,21,22] This feasibility has been validated, at least, by the findings that circadian rhythm-dependent intervention, e.g., timed cyclin-dependent kinase suppression or meal timing[23,24], differentially influenced the efficiency of cancer inhibition. Anti-metabolism-based evening chemotherapy for children with acute lymphoma resulted in a significant increase in 5-year survival rate compared with morning chemotherapy[27,28] Together, these studies clearly demonstrate circadian clocks as important targets for effective cancer intervention. The present study investigated the link between circadian clock dysregulation and PFKFB3 expression in human tongue cancer and tongue cancerous cells, and demonstrated a critical role for PFKFB3 in controlling tongue cancer by responding to circadian clock outputs
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
