Epigenetic regulation of integrin β6 transcription induced by TGF‐β1 in human oral squamous cell carcinoma cells

Abstract

Overexpression of integrin αvβ6 is believed to play an important role in the invasion and metastasis of oral squamous cell carcinoma (OSCC). However, little is known about the molecular mechanisms leading to αvβ6 upregulation in OSCC. As the integrin β6 (ITGB6) is the only partner with αv, the expression of αvβ6 is dependent on ITGB6, it is, therefore, pivotal to investigate the mechanisms underlying ITGB6 overexpression in OSCC. We previously reported the cloning and characterization of human ITGB6 gene. In the current study, we further investigated the molecular mechanisms of ITGB6 expression and the upregulation by carcinogenesis related cytokine-transforming growth factor-β1 (TGF-β1) in OSCC cells. We first demonstrated that TGF-β1 can induce ITGB6 mRNA and protein express in a time and concentration dependent manner, and the induced-ITGB6 mRNA was not due to increase the mRNA stability, but regulated at transcriptional level. By using a luciferase reporter assay, site-mutation, RNA interference, and chromatin immunoprecipitation assay, we revealed for the first time that JunB, a member of the activator protein-1 (AP-1) family, is involved in the positive regulation to the ITGB6 transcription induced by TGF-β1 in OSCC cells. Furthermore, our data also demonstrated that histone acetyltransferase (HAT) CBP mediated histone H3 and H4 hyperacetylation, and RNA Polymerase II recruitment to ITGB6 promoter, facilitated the binding of transcription factor JunB to ITGB6 promoter after TGF-β1 stimulation. Collectively, these findings demonstrate that JunB and CBP-mediated histone hyperacetylation are responsible for TGF-β1 induced ITGB6 transcription in OSCC cells, suggesting that epigenetic mechanisms are responsible for the active transcription expression of ITGB6 induced by TGF-β1 in OSCC cells.

Intermittent compressive force promotes osteogenic differentiation in human periodontal ligament cells by regulating the transforming growth factor-β pathway

“…In a mouse dental papilla mesenchymal cell line, integrin β6 bound to dentin sialoprotein and subsequently induced cell attachment, migration, and Dmp1 and Dspp mRNA expression 50 , suggesting that integrin β6 is involved in the regulation of dental mesenchymal cell behavior. TGF-β1 positively regulated ITGB6 expression in oral cancer cells and gingival keratinocytes that may participate in cancer invasion and periodontal inflammation, respectively 51,52 . Our RNA sequencing data revealed increased ITGB6 mRNA levels concurrent with the upregulation of TGFB1 mRNA in ICF treatment.…”

Construction and analysis of the lncRNA-miRNA-mRNA network based on competitive endogenous RNA reveal functional lncRNAs in oral cancer

“…Another GO term, regulation of transcription by RNA polymerase II, also had a connection with oral cancer. Xu et al provided evidence that Histone acetylation and RNA polymerase II recruitment on the integrin β6 promoter are involved in the TGF-β1-induced integrin β6 expression in OSCC cells, which would then promote tumorigenesis and metastasis (63). Additionally, ten KEGG pathways, including the human papillomavirus infection, ECMreceptor interaction, small cell lung cancer, TGF-β signaling pathway, PI3K-Akt signaling pathway and TNF signaling pathway were determined.…”

Histone modifications in oral squamous cell carcinoma and oral potentially malignant disorders

“…Acetylated H3 caused by p300 elevation was nitric oxide signal dependent (Arif et al, ). H3ac and H4ac induced by CBP together with RNA Pol II recruit were associated with transforming growth factor (TGF)‐β1‐induced transcription of integrin beta‐6 precursor (Xu et al, ). The upregulated EP300/CBP mutations may attenuate differentiation to enable the establishment of HNSCC cell cultures (Martin et al, ).…”

“…The FDA‐approved drug for refractory/relapsed multiple myeloma hydroxamate analog panobinostat (LBH589) induced histone H3 and H4 hyperacetylation (Xu et al, ). LBH589 inhibited cellular growth, resulted in G1 phase arrest, and reinforced apoptosis mediated by transcription factor specificity protein 1 (Sp1) suppression.…”