Hypoxia-inducible CircPFKFB4 Promotes Breast Cancer Progression by Facilitating the CRL4^DDB2 E3 Ubiquitin Ligase-mediated p27 Degradation

Abstract

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, HIF1α 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 CRL4 DDB2 E3 ubiquitin ligase assembly, resulting in p27 ubiquitination and BC progression under hypoxia. Our findings revealed a novel interaction between circPFKFB4 and the CRL4 DDB2 E3 ubiquitin ligase, suggesting that circPFKFB4 might serve as a promising biomarker and therapeutic target for BC.

DDB2 promotes melanoma cell growth by transcriptionally regulating the expression of KMT2A and predicts a poor prognosis

“…DDB2 inhibits antioxidant genes by inducing histone 3 lysine 9 trimethylation (H3K9me3) of histones, thereby leading to accumulation of reactive oxygen species (ROS), inducing premature aging, and inhibiting the occurrence of skin tumors. DDB2 deficiency can lead to the suppression of premature aging caused by exogenous oxidative stress and/or DNA damage, reducing ROS accumulation 21 . Our previous study showed that KMT2A promotes the invasion and metastasis of melanoma cells, therefore this study was not repeated 35 .…”

“…DDB2 deficiency can lead to the suppression of premature aging caused by exogenous oxidative stress and/or DNA damage, reducing ROS accumulation. 21 Our previous study showed that KMT2A promotes the invasion and metastasis of melanoma cells, therefore this study was not repeated. 35 However, we evaluated the relationship between DDB2 expression and clinical prognosis and found that high expression of DDB2 and KMT2A in patients with melanoma predicted poor prognosis.…”

“…18,19 It affects the occurrence and development of tumors through many processes, such as DNA damage repair, cell proliferation and apoptosis, cell invasion and metastasis, cell premature aging, and tumor stem cell popularization. 20,21 Many studies have shown that structural changes and dysfunction of DDB2 can lead to a variety of diseases and cancers, such as breast cancer, 22 xeroderma pigmentosum, 23 head and neck squamous cell carcinoma, 19 hepatocellular carcinoma, 24 skin cancer, 25 lung cancers, 26 and melanoma. 16 Recent studies have shown that the hypoxia-induced circular 6-phosphofructose-2-kinase/fructose-2,6bisphosphatase 4 (circPFKFB4) promotes breast cancer progression by facilitating p27 degradation by the CRL4 DDB2 E3 ubiquitin ligase assembly.…”

CircNFATC3 promotes the proliferation of gastric cancer through binding to IGF2BP3 and restricting its ubiquitination to enhance CCND1 mRNA stability

“…Similar to our results, previous studies have indicated that other circRNAs could also regulate protein expression. For example, circPFKFB4 inhibits DDB2 degradation in breast cancer [ 47 ] and circ_0006156 binds and stabilizes S100A9 in prostate cancer [ 48 ]. These data indicated a role for circRNAs in the post-transcriptional regulation of gene expression.…”

Hypoxia-driven ncRNAs in breast cancer

“…Hypoxia promotes breast cancer proliferation and progression by inducing certain circRNAs as well. For instance, upon transcriptional activation through HIF1α, circPFKFB4 binds to damage specific DNA binding protein 1 (DDB1)/DDB2 and aids in cullin-ring ligase-4 (CRL4)-DDB2 ubiquitin ligase assembly, which in turn promotes cancer cell proliferation by specifically increasing the degradation of tumor suppressor p27 ( 74 ). circWSB1 expression correlates with poor prognosis and clinical outcome in breast cancer patients.…”