Abstract
Background: Hypoxia induces a series of cellular adaptive responses that enable to promote inflammation and cancer development. However, only few have been fully characterized about the roles of long noncoding RNAs (lncRNAs) in hypoxia-associated cancer progression. Methods: The involvement of lncRNAs in hypoxia-related cancer progression was screened by qRT-PCR. Based on the public databases and integrating bioinformatics analysis, the alteration of prostate cancer associated transcript-1 (PCAT-1) in breast cancer tissues was detected and validated in a cohort of breast cancer tissues. Overexpression and knocking down experiments were performed to uncover the biological roles of PCAT-1 on cell hypoxia-associated phenotypes and biological behaviors. RNA immunoprecipitation (RIP) and RNA pull-down were carried out to reveal the physical interaction between PCAT-1 and receptor of activated protein-C kinase-1 (RACK1). Moreover, xenograft mouse models were used to evaluate the influence of PCAT-1 on cancer progression and metastasis in vivo.Results: We identified PCAT-1 as a hypoxia-inducible lncRNA that regulated the hypoxia-inducible factor-1α (HIF-1α) stability, crucial for cancer progression. Extensive analyses of clinical data indicated that PCAT-1 was elevated in breast cancer patients and was associated with pathological grade, tumor size and poor clinical outcomes. Through gain and loss of function experiments, we found that PCAT-1 promoted hypoxia-associated breast cancer progression including growth, migration, invasion, colony formation, and metabolic regulation. Mechanistically, PCAT-1 directly interacted with RACK1 protein and prevented RACK1 from binding to HIF-1α, thus protecting HIF-1α from RACK1-induced oxygen-independent degradation.Conclusions: These findings provide a new insight into lncRNA-mediated mechanisms for HIF-1α stability and suggest that a novel role of PCAT-1 as a potential therapeutic target for breast cancer.
Hypoxia-Inducible Factor 1α Regulates the Transforming Growth Factor β1/SMAD Family Member 3 Pathway to Promote Breast Cancer Progression