Regulation of the adaptation to ER stress by KLF4 facilitates melanoma cell metastasis via upregulating NUCB2 expression

Abstract

BackgroundAdaptation to ER stress has been indicated to play an important role in resistance to therapy in human melanoma. However, the relationship between adaptation to ER stress and cell metastasis in human melanoma remains unclear.MethodsThe relationship of adaptation to ER stress and cell metastasis was investigated using transwell and mouse metastasis assays. The potential molecular mechanism of KLF4 in regulating the adaptation to ER stress and cell metastasis was investigated using RNA sequencing analysis, q-RT-PCR and western blot assays. The transcriptional regulation of nucleobindin 2 (NUCB2) by KLF4 was identified using bioinformatic analysis, luciferase assay, and chromatin immunoprecipitation (ChIP). The clinical significance of KLF4 and NUCB2 was based on human tissue microarray (TMA) analysis.ResultsHere, we demonstrated that KLF4 was induced by ER stress in melanoma cells, and increased KLF4 inhibited cell apoptosis and promoted cell metastasis. Further mechanistic studies revealed that KLF4 directly bound to the promoter of NUCB2, facilitating its transcription. Additionally, an increase in KLF4 promoted melanoma ER stress resistance, tumour growth and cell metastasis by regulating NCUB2 expression in vitro and in vivo. Elevated KLF4 was found in human melanoma tissues, which was associated with NUCB2 expression.ConclusionOur data revealed that the promotion of ER stress resistance via the KLF4-NUCB2 axis is essential for melanoma cell metastasis, and KLF4 may be a promising specific target for melanoma therapy.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0842-z) contains supplementary material, which is available to authorized users.

ITIH5, a p53-responsive gene, inhibits the growth and metastasis of melanoma cells by downregulating the transcriptional activity of KLF4

“…Many studies have shown that KLF4 is an important oncogene in melanoma 24 – 26 . We therefore wanted to determine whether ITIH5 suppresses melanoma malignancy by downregulating KLF4.…”

“…KLF4 is a well-known transcription factor that regulates tumorigenesis in a manner dependent on its transcriptional activity 27 . Based on this, we assessed the effect of ITIH5 on the expression of NUCB2, a known target gene of KLF4, in melanoma cells 24 . Compared with those of the control cells, the mRNA and protein levels of NUCB2 decreased when ITIH5 was overexpressed (Fig.…”

Helicobacter pylori CagA promotes the malignant transformation of gastric mucosal epithelial cells through the dysregulation of the miR‐155/KLF4 signaling pathway

“…We previously discovered that the knockout of KLF4 in gastric epithelial cells, combined with the chemical reagent N ‐methyl‐ N ‐nitrosourea, could induce the malignant transformation of the mouse gastric sinus . Subsequently, it was further demonstrated that KLF4 was a tumor suppressor gene in GC because KLF4 was reduced dramatically in GC and the exogenous expression of KLF4 promoted cell apoptosis and restricted tumor formation . Therefore, we hypothesized that there was a causal relationship between KLF4 and CagA.…”

Systems analysis of barrier molecule and ARNT-related gene expression regulation in melanoma

“…KLF4 has not been well studied in melanomas; however, what little is known suggests a pro-tumorigenic role. 29,30 Other studies support roles of KLF4 in decreasing apoptosis, 29,31 and supporting melanoma cell stemness. 32 Additionally, KLF4 knockout is associated with loss of barrier function and aberrations in keratinocyte differentiation in the skin and cornea.…”