Hypoxia-inducible CircPFKFB4 Promotes Breast Cancer Progression by Facilitating the CRL4DDB2 E3 Ubiquitin Ligase-mediated p27 Degradation

作者全名："Chen, Hang; Yang, Rui; Xing, Lei; Wang, Bin; Liu, Dawei; Ou, Xiaoqiang; Deng, Yumei; Jiang, Rong; Chen, Junxia"

作者地址："[Chen, Hang; Yang, Rui; Wang, Bin; Ou, Xiaoqiang; Deng, Yumei; Chen, Junxia] Chongqing Med Univ, Dept Cell Biol & Genet, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China; [Xing, Lei] Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrine & Breast Surg, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China; [Wang, Bin] Army Med Univ, Daping Hosp, Dept Oncol, 10 Changjiang Branch Rd, Chongqing 400042, Peoples R China; [Liu, Dawei] Chongqing Med Univ, Yongchuan Hosp, Dept Anesthesiol, 439 XuanHua Rd, Chongqing 402160, Peoples R China; [Jiang, Rong] Chongqing Med Univ, Lab Stem Cells & Tissue Engn, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China"

通信作者："Chen, JX (通讯作者)，Chongqing Med Univ, Dept Cell Biol & Genet, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China."

来源：INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000809715600002

JCR分区：Q1

影响因子：9.2

年份：2022

卷号：18

期号：9

开始页：3888

结束页：3907

文献类型：Article

关键词：Hypoxia; Breast cancer; circPFKFB4; CRL4DDB2 E3 ubiquitin ligase; p27

摘要："Hypoxic microenvironment and circular RNAs (circRNAs) have shown critical implications in breast cancer (BC) progression. However, the specific functions and underlying mechanisms of circRNAs in BC under hypoxia remain largely unknown. We first screened for differentially expressed circRNAs in normoxic and hypoxic MCF-7 cells using circRNA microarray. A novel hypoxia-induced circRNA, circPFKFB4, was identified. Clinical investigation showed that circPFKFB4 was highly expressed in BC tissues and cell lines, and its overexpression was positively correlated with the advanced clinical stage and poor prognosis of BC patients. Functionally, circPFKFB4 promoted the proliferation of BC cells both in vitro and in vivo. Mechanistically, HIF1?? bound to hypoxia response elements in the promoter region of the PFKFB4 gene to facilitate the biogenesis of circPFKFB4 under hypoxia. Hypoxia-induced circPFKFB4 directly bound to both DDB1 and DDB2 and promoted the CRL4DDB2 E3 ubiquitin ligase assembly, resulting in p27 ubiquitination and BC progression under hypoxia. Our findings revealed a novel interaction between circPFKFB4 and the CRL4DDB2 E3 ubiquitin ligase, suggesting that circPFKFB4 might serve as a promising biomarker and therapeutic target for BC."

基金机构："National Natural Science Foundation of China [82173170, 82103089]; project of the top-notch talent cultivation program for the graduate students of Chongqing Medical University [BJRC202102]"

基金资助正文：This work was supported by the National Natural Science Foundation of China (Nos. 82173170 and 82103089) and the project of the top-notch talent cultivation program for the graduate students of Chongqing Medical University (No. BJRC202102) .