KLF5 promotes hypoxia-induced survival and inhibits apoptosis in non-small cell lung cancer cells via HIF-1α

Abstract

Abstract. Transcription factor Krüppel-like factors 5 (KLF5) is overexpressed in a wide range of tumor tissues and acts as a prognostic factor in cancer. However, the role of KLF5 in non-small cell lung cancer is not clear. Hypoxia plays a vital part in the development of cancer via hypoxia-inducible factor 1 (HIF-1). Our study showed that hypoxia (1% O 2 ) increased cell viability, clonality and proliferation and inhibited cell apoptosis in A549 cells. The expression of HIF-1α and KLF5 was increased time-dependently in hypoxia. Using small interfering RNA (siRNA) targeting KLF5 or HIF-1α, we demonstrated that KLF5 or HIF-1α knockdown inhibited hypoxia-induced cell survival and promoted cell apoptosis by actively downregulating cyclin B1, survivin and upregulating caspase-3. Given the similar effect of KLF5 and HIF-1α on cell survival, an attempt was made to investigate the putative interaction of them in hypoxia. KLF5 was revealed to co-immunoprecipitate with HIF-1α and hypoxia increased the amount of KLF5 and HIF-1α complex. Moreover, silencing of KLF5 decreased HIF-1α expression while KLF5 was not affected by HIF-1α inhibition in hypoxia, confirming the effect of KLF5 on upregulation of HIF-1α. In conclusion, this study identified hypoxia as a tumor promoter by triggering KLF5 → HIF-1α → cyclin B1/survivin/caspase-3 in lung cancer cells.

C5a induces A549 cell proliferation of non-small cell lung cancer via GDF15 gene activation mediated by GCN5-dependent KLF5 acetylation

“…To date, KLF5 binding to GC boxes on gene promoters and regulating gene transcription have been reported [14, 42]. Moreover, it is also demonstrated that GCN5 can amplify transcription factor effect [17, 18, 43].…”

“…It is well known that cell proliferation is associated with the upregulation of transcription factors, transcriptional co-activators and pro-proliferation molecules in response to extracellular stimuli [13, 14]. Reportedly, kruppel-like factor 5 (KLF5), as a transcription factor, can boost breast cancer cell proliferation [15], and activate sox4 or HIF-1α transcription via binding to GC-rich DNA sequences, resulting in lung cancer proliferation [16].…”

miR‐214‐5p targets KLF5 and suppresses proliferation of human hepatocellular carcinoma cells

“…Krüppel‐like factor 5 (KLF5) is a member of the Krüppel‐like factor (KLF) family and plays crucial roles in various cellular processes including cell proliferation, apoptosis, migration, and differentiation . KLF5 consists a conserved zinc finger domain and is capable to regulate the expression of several downstream target genes, such as cyclin D1, cyclin B1, fibroblast growth factor binding protein 1, SOX4, Hypoxia‐inducible factor 1 α, epithelial growth factor receptor, tumor necrosis factor‐α (TNF‐α)‐induced protein 2, and survivin . Besides that, KLF5 expression can be regulated by miRNAs or posttranslation modification .…”

Severe hypoxia and malnutrition collectively contribute to scar fibroblast inhibition and cell apoptosis

“…Our results demonstrated that moderate hypoxia (5% O 2 ) and severe hypoxia (0.5% O 2 ) could increase cell viability, which is correlated with higher expression of HIF‐1. As well‐known, HIF‐1 is activated under hypoxia stress and plays a central role for cell survival . It can activate many genes transcription such as TGF‐β 1 and VEGF, which are involved in angiogenesis and collagen production and promote hypertrophic scar formation.…”