PER1 as a Tumor Suppressor Attenuated in the Malignant Phenotypes of Breast Cancer Cells

Abstract

Yinfeng Liu,1,2 Jun Hao,3 Guanli Yuan,4 Mengyu Wei,1 Yuhui Bu,1 Tingting Jin,3 Li Ma1 1Department of Breast Disease Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China; 2Department of Breast Surgery, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei, 066000, People’s Republic of China; 3Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei, 066000, People’s Republic of ChinaCorrespondence: Li MaDepartment of Breast Disease Center, The Fourth Hospital of Hebei Medical University, No. 169, Tianshan Street, Shijiazhuang, Hebei, 050000, People’s Republic of ChinaTel [phone]Email [email protected]: Circadian clock genes play a crucial role in physiological and pathological processes, and their aberrant expressions were involved in various human cancers. The objective of this study was to investigate the expression level of Period circadian regulator 1 (PER1), an important circadian clock gene, and its biological roles in the development and progression of breast cancer.Methods: The expression level of PER1 in breast cancer samples was analyzed using the Oncomine database, and the correlation between PER1 expression and clinicopathologic parameters was assessed by bc-GenExMiner v4.5. In addition, Kaplan–Meier plotter database was used to determine the prognostic significance of PER1 expression for breast cancer patients. The expressions of PER1 in breast cancer tissues and cells were validated by Western blot. The loss-or-gain assay of PER1 was conducted to investigate the effects of its expression on cell proliferation, migration and invasion of breast cancer. The relationship between PER1 expression and epigenetic modifications was further explored by Western blot.Results: The results of the bioinformatics analysis revealed that the expression level of PER1 was markedly reduced in breast cancer tissues (P< 0.001), and patients with high expression of PER1 had a better overall survival (HR:0.78, 95% CI:0.63– 0.97, P=0.026) and recurrence-free survival (HR:0.83, 95% CI:0.75– 0.93, P=0.001) than those with low expression. The assay of gene loss-or-gain indicated that downregulation of PER1 expression markedly promoted cell proliferation, migration and invasion (P< 0.05), whereas these malignant phenotypes of breast cancer cells were inhibited by PER1 overexpression (P< 0.05). Further studies showed that trichostatin A (TSA), a histone deacetylase inhibitor, induced the expression of PER1 protein in breast cancer cells (P< 0.05).Conclusion: PER1 functions as a tumor suppressor in the development and progression of breast cancer, and its expression silencing might be regulated by epigenetic modifications.Keywords: breast cancer, circadian clock gene, Period circadian regulator 1, PER1, tumor suppressor

Keywords

• breast cancer
• circadian clock gene
• period circadian regulator 1
• per1
• tumor suppressor