The PER1/HIF-1alpha negative feedback loop promotes ferroptosis and inhibits tumor progression in oral squamous cell carcinoma

作者全名："Yang, Yixin; Tang, Hong; Zheng, Jiawen; Yang, Kai"

作者地址："[Yang, Yixin; Tang, Hong; Zheng, Jiawen; Yang, Kai] Chongqing Med Univ, Dept Oral & Maxillofacial Surg, Affiliated Hosp 1, 1,Youyi Rd, Chongqing 400016, Peoples R China"

通信作者："Yang, K (通讯作者)，Chongqing Med Univ, Dept Oral & Maxillofacial Surg, Affiliated Hosp 1, 1,Youyi Rd, Chongqing 400016, Peoples R China."

来源：TRANSLATIONAL ONCOLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000820885800007

JCR分区：Q1

影响因子：5

年份：2022

卷号：18

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Ferroptosis; Oral cancer; Period 1; HIF-1alpha; Clock genes

摘要："Current studies have proven that the decreased expression of the core circadian clock gene Period 1 (PER1) is closely related to the occurrence and progression of multiple malignant tumors, including oral squamous cell carcinoma (OSCC). But the mechanism involved is largely unknown. In this study, we found that PER1 was negatively correlated with the expression of the key ferroptosis-regulated proteins glutathione peroxidase (GPX4) and hypoxia inducible factor-1alpha (HIF-1 alpha) in OSCC tissues. The expression of the ferroptosis related proteins GPX4, solute carrier family 7 member 11 (SLC7A11) and transferrin receptor (TFRC) and the levels of glutathione (GSH), malondialdehyde (MDA), reactive oxygen species (ROS) and Fe2+ were detected in OSCC cells with overexpression or silencing of PER1. Mitochondrial morphology changes were observed. We found that PER1 promotes ferroptosis depending on HIF-1 alpha in OSCC cells. In vivo tumorigenicity assays proved that PER1 over expression inhibits HIF-1 alpha, promotes ferroptosis and suppresses OSCC growth. Mechanistically, coimmunoprecipitation and cycloheximide tracking assays proved that PER1 binds to HIF-1 alpha to promote HIF-1 alpha protein degradation. ChIP and dual luciferase reporter assays proved that HIF-1 alpha binds to the PER1 promoter leading to feedback inhibition of PER1 transcription. Our findings suggest that targeting the PER1/HIF-1 alpha negative feedback loop may provide a new strategy for OSCC treatment."

基金机构："Chongqing Talents.Innovation Leading Talents Project [CQYC20200303128]; Natural Science Foundation of Chongqing, China [cstc2018jcyjAX0208]"

基金资助正文："This work was supported by Chongqing Talents.Innovation Leading Talents Project (CQYC20200303128); Natural Science Foundation of Chongqing, China (cstc2018jcyjAX0208)."