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http://dx.doi.org/10.5352/JLS.2017.27.10.1225

Circadian Clock Genes, PER1 and PER2, as Tumor Suppressors  

Son, Beomseok (Department of Integrated Biological Science, Pusan National University)
Do, Hyunhee (Department of Biology Education, Korea National University of Education)
Kim, EunGi (Department of Integrated Biological Science, Pusan National University)
Youn, BuHyun (Department of Integrated Biological Science, Pusan National University)
Kim, Wanyeon (Department of Biology Education, Korea National University of Education)
Publication Information
Journal of Life Science / v.27, no.10, 2017 , pp. 1225-1231 More about this Journal
Abstract
Disruptive expression patterns of the circadian clock genes are highly associated with many human diseases, including cancer. Cell cycle and proliferation is linked to a circadian rhythm; therefore, abnormal clock gene expression could result in tumorigenesis and malignant development. The molecular network of the circadian clock is based on transcriptional and translational feedback loops orchestrated by a variety of clock activators and clock repressors. The expression of 10~15% of the genome is controlled by the overall balance of circadian oscillation. Among the many clock genes, Period 1 (Per1) and Period 2 (Per2) are clock repressor genes that play an important role in the regulation of normal physiological rhythms. It has been reported that PER1 and PER2 are involved in the expression of cell cycle regulators including cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors. In addition, correlation of the down-regulation of PER1 and PER2 with development of many cancer types has been revealed. In this review, we focused on the molecular function of PER1 and PER2 in the circadian clock network and the transcriptional and translational targets of PER1 and PER2 involved in cell cycle and tumorigenesis. Moreover, we provide information suggesting that PER1 and PER2 could be promising therapeutic targets for cancer therapies and serve as potential prognostic markers for certain types of human cancers.
Keywords
Circadian rhythm; clock gene; cell cycle; PER1; PER2; tumor suppressor;
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1 Fu, L., Pelicano, H., Liu, J., Huang, P. and Lee, C. 2002. The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 111, 41-50.   DOI
2 Zhao, H., Zeng, Z. L., Yang, J., Jin, Y., Qiu, M. Z., Hu, X. Y., Han, J., Liu, K. Y., Liao, J. W., Xu, R. H. and Zou, Q. F. 2014. Prognostic relevance of Period1 (Per1) and Period2 (Per2) expression in human gastric cancer. Int. J. Clin. Exp. Pathol. 7, 619-630.
3 Mteyrek, A., Filipski, E., Guettier, C., Okyar, A. and Levi, F. 2016. Clock gene Per2 as a controller of liver carcinogenesis. Oncotarget 7, 85832-85847.
4 Okabe, T., Kumagai, M., Nakajima, Y., Shirotake, S., Kodaira, K., Oyama, M., Ueno, M. and Ikeda, M. 2014. The impact of HIF1alpha on the Per2 circadian rhythm in renal cancer cell lines. PLoS One 9, e109693.   DOI
5 Repouskou, A. and Prombona, A. 2016. c-MYC targets the central oscillator gene Per1 and is regulated by the circadian clock at the post-transcriptional level. Biochim. Biophys. Acta. 1859, 541-552.   DOI
6 Reppert, S. M. and Weaver, D. R. 2002. Coordination of circadian timing in mammals. Nature 418, 935-941.   DOI
7 Shearman, L. P., Sriram, S., Weaver, D. R., Maywood, E. S., Chaves, I., Zheng, B., Kume, K., Lee, C. C., van der Horst, G. T., Hastings, M. H. and Reppert, S. M. 2000. Interacting molecular loops in the mammalian circadian clock. Science 288, 1013-1019.   DOI
8 Reszka, E., Przybek, M., Muurlink, O. and Peplonska, B. 2017. Circadian gene variants and breast cancer. Cancer Lett. 390, 137-145.   DOI
9 Richardson, A. L., Wang, Z. C., De Nicolo, A., Lu, X., Brown, M., Miron, A., Liao, X., Iglehart, J. D., Livingston, D. M. and Ganesan, S. 2006. X chromosomal abnormalities in basal- like human breast cancer. Cancer Cell 9, 121-132.   DOI
10 Scheiermann, C., Kunisaki, Y. and Frenette, P. S. 2013. Circadian control of the immune system. Nat. Rev. Immunol. 13, 190-198.   DOI
11 Siepka, S. M., Yoo, S. H., Park, J., Song, W., Kumar, V., Hu, Y., Lee, C. and Takahashi, J. S. 2007. Circadian mutant Overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression. Cell 129, 1011-1023.   DOI
12 Wood, P. A., Yang, X. and Hrushesky, W. J. 2009. Clock genes and cancer. Integr. Cancer Ther. 8, 303-308.
13 Storch, K. F., Lipan, O., Leykin, I., Viswanathan, N., Davis, F. C., Wong, W. H. and Weitz, C. J. 2002. Extensive and divergent circadian gene expression in liver and heart. Nature 417, 78-83.   DOI
14 Su, X., Chen, D., Yang, K., Zhao, Q., Zhao, D., Lv, X. and Ao, Y. 2017. The circadian clock gene PER2 plays an important role in tumor suppression through regulating tumor-associated genes in human oral squamous cell carcinoma. Oncol. Rep. 38, 472-480.   DOI
15 Sun, C. M., Huang, S. F., Zeng, J. M., Liu, D. B., Xiao, Q., Tian, W. J., Zhu, X. D., Huang, Z. G. and Feng, W. L. 2010. Per2 inhibits k562 leukemia cell growth in vitro and in vivo through cell cycle arrest and apoptosis induction. Pathol. Oncol. Res. 16, 403-411.   DOI
16 Takahashi, J. S., Hong, H. K., Ko, C. H. and McDearmon, E. L. 2008. The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat. Rev. Genet. 9, 764-775.   DOI
17 Tamiya, H., Ogawa, S., Ouchi, Y. and Akishita, M. 2016. Rigid Cooperation of Per1 and Per2 proteins. Sci. Rep. 6, 32769.   DOI
18 Xia, H. C., Niu, Z. F., Ma, H., Cao, S. Z., Hao, S. C., Liu, Z. T. and Wang, F. 2010. Deregulated expression of the Per1 and Per2 in human gliomas. Can. J. Neurol. Sci. 37, 365-370.   DOI
19 Zeng, Z. L., Wu, M. W., Sun, J., Sun, Y. L., Cai, Y. C., Huang, Y. J. and Xian, L. J. 2010. Effects of the biological clock gene Bmal1 on tumour growth and anti-cancer drug activity. J. Biochem. 148, 319-326.   DOI
20 Zhanfeng, N., Yanhui, L., Zhou, F., Shaocai, H., Guangxing, L. and Hechun, X. 2015. Circadian genes Per1 and Per2 increase radiosensitivity of glioma in vivo. Oncotarget 6, 9951-9958.   DOI
21 Chen, S. T., Choo, K. B., Hou, M. F., Yeh, K. T., Kuo, S. J. and Chang, J. G. 2005. Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers. Carcinogenesis 26, 1241-1246.   DOI
22 Bae, K., Jin, X., Maywood, E. S., Hastings, M. H., Reppert, S. M. and Weaver, D. R. 2001. Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock. Neuron 30, 525-536.   DOI
23 Bhattacharjee, A., Richards, W. G., Staunton, J., Li, C., Monti, S., Vasa, P., Ladd, C., Beheshti, J., Bueno, R., Gillette, M., Loda, M., Weber, G., Mark, E. J., Lander, E. S., Wong, W., Johnson, B. E., Golub, T. R., Sugarbaker, D. J. and Meyerson, M. 2001. Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc. Natl. Acad. Sci. USA 98, 13790-13795.   DOI
24 Cadenas, C., van de Sandt, L., Edlund, K., Lohr, M., Hellwig, B., Marchan, R., Schmidt, M., Rahnenfuhrer, J., Oster, H. and Hengstler, J. G. 2014. Loss of circadian clock gene expression is associated with tumor progression in breast cancer. Cell Cycle 13, 3282-3291.   DOI
25 Cao, Q., Gery, S., Dashti, A., Yin, D., Zhou, Y., Gu, J. and Koeffler, H. P. 2009. A role for the clock gene per1 in prostate cancer. Cancer Res. 69, 7619-7625.   DOI
26 Chen, B., Tan, Y., Liang, Y., Li, Y., Chen, L., Wu, S., Xu, W., Wang, Y., Zhao, W. and Wu, J. 2017. Per2 participates in AKT-mediated drug resistance in A549/DDP lung adenocarcinoma cells. Oncol. Lett. 13, 423-428.   DOI
27 Dardente, H. and Cermakian, N. 2007. Molecular circadian rhythms in central and peripheral clocks in mammals. Chronobiol. Int. 24, 195-213.   DOI
28 Dibner, C., Schibler, U. and Albrecht, U. 2010. The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu. Rev. Physiol. 72, 517-549.   DOI
29 Gery, S., Komatsu, N., Baldjyan, L., Yu, A., Koo, D. and Koeffler, H. P. 2006. The circadian gene per1 plays an important role in cell growth and DNA damage control in human cancer cells. Mol. Cell 22, 375-382.   DOI
30 Gachon, F. 2007. Physiological function of PARbZip circadian clock-controlled transcription factors. Ann. Med. 39, 562-571.   DOI
31 Gotoh, T., Vila-Caballer, M., Santos, C. S., Liu, J., Yang, J. and Finkielstein, C. V. 2014. The circadian factor Period 2 modulates p53 stability and transcriptional activity in unstressed cells. Mol. Biol. Cell 25, 3081-3093.   DOI
32 Gotoh, T., Kim, J. K., Liu, J., Vila-Caballer, M., Stauffer, P. E., Tyson, J. J. and Finkielstein, C. V. 2016. Model-driven experimental approach reveals the complex regulatory distribution of p53 by the circadian factor Period 2. Proc. Natl. Acad. Sci. USA 113, 13516-13521.   DOI
33 Grechez-Cassiau, A., Rayet, B., Guillaumond, F., Teboul, M. and Delaunay, F. 2008. The circadian clock component BMAL1 is a critical regulator of p21WAF1/CIP1 expression and hepatocyte proliferation. J. Biol. Chem. 283, 4535-4542.   DOI
34 Green, C. B., Takahashi, J. S. and Bass, J. 2008. The meter of metabolism. Cell 134, 728-742.   DOI
35 Hsu, C. M., Lin, P. M., Lai, C. C., Lin, H. C., Lin, S. F. and Yang, M. Y. 2014. PER1 and CLOCK: potential circulating biomarkers for head and neck squamous cell carcinoma. Head Neck 36, 1018-1026.   DOI
36 Liu, B., Xu, K., Jiang, Y. and Li, X. 2014. Aberrant expression of Per1, Per2 and Per3 and their prognostic relevance in non-small cell lung cancer. Int. J. Clin. Exp. Pathol. 7, 7863-7871.
37 Huber, A. L., Papp, S. J., Chan, A. B., Henriksson, E., Jordan, S. D., Kriebs, A., Nguyen, M., Wallace, M., Li, Z., Metallo, C. M. and Lamia, K. A. 2016. CRY2 and FBXL3 Cooperatively Degrade c-MYC. Mol. Cell 64, 774-789.   DOI
38 Jung-Hynes, B., Huang, W., Reiter, R. J. and Ahmad, N. 2010. Melatonin resynchronizes dysregulated circadian rhythm circuitry in human prostate cancer cells. J. Pineal Res. 49, 60-68.
39 Lengyel, Z., Lovig, C., Kommedal, S., Keszthelyi, R., Szekeres, G., Battyani, Z., Csernus, V. and Nagy, A. D. 2013. Altered expression patterns of clock gene mRNAs and clock proteins in human skin tumors. Tumour Biol. 34, 811-819.   DOI
40 Lowrey, P. L. and Takahashi, J. S. 2004. Mammalian circadian biology: elucidating genome-wide levels of temporal organization. Annu. Rev. Genomics Hum. Genet. 5, 407-441.   DOI
41 Matsuo, T., Yamaguchi, S., Mitsui, S., Emi, A., Shimoda, F. and Okamura, H. 2003. Control mechanism of the circadian clock for timing of cell division in vivo. Science 302, 255-259.   DOI
42 Mokros, L., Karbownik, M. S., Nowakowska-Domagala, K., Szemraj, J., Wieteska, L., Wozniak, K., Witusik, A., Antczak, A. and Pietras, T. 2016. Haloperidol, but not olanzapine, may affect expression of PER1 and CRY1 genes in human glioblastoma cell line. Biol. Rhythm Res. 47, 865-871.   DOI
43 Hua, H., Wang, Y., Wan, C., Liu, Y., Zhu, B., Yang, C., Wang, X., Wang, Z., Cornelissen-Guillaume, G. and Halberg, F. 2006. Circadian gene mPer2 overexpression induces cancer cell apoptosis. Cancer Sci. 97, 589-596.   DOI
44 Fu, X. J., Li, H. X., Yang, K., Chen, D. and Tang, H. 2016. The important tumor suppressor role of PER1 in regulating the cyclin-CDK-CKI network in SCC15 human oral squamous cell carcinoma cells. Onco Targets Ther. 9, 2237-2245.
45 Mazzoccoli, G., Panza, A., Valvano, M. R., Palumbo, O., Carella, M., Pazienza, V., Biscaglia, G., Tavano, F., Di Sebastiano, P., Andriulli, A. and Piepoli, A. 2011. Clock gene expression levels and relationship with clinical and pathological features in colorectal cancer patients. Chronobiol. Int. 28, 841-851.   DOI