title: PFKFB3 Control of Cancer Growth by Responding to Circadian Clock Outputs.
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.
authors.affiliation: Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.|Department of Nutrition and Food Science, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
authors.forename: Qingming
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Honggui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Yu
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.|Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Huo
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Chaodong
authors.initials: C
authors.lastname: Wu
mesh_terms: D000328:Adult; D017209:Apoptosis; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation; D057906:Circadian Clocks / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D025481:Phosphofructokinase-2 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014062:Tongue Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015533:Transcriptional Activation
chemical_list: D019344:Lactic Acid; D056926:CLOCK Proteins; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2