Abstract
Melanoma is one of the most immunogenic tumors and has the highest potential to elicit specific adaptive antitumor immune responses. Immune cells induce apoptosis of cancer cells either by soluble factors or by triggering cell-death pathways. Melanoma cells exploit multiple mechanisms to escape immune system tumoricidal control. FKBP51 is a relevant pro-oncogenic factor of melanoma cells supporting NF-κB-mediated resistance and cancer stemness/invasion epigenetic programs. Herein, we show that FKBP51-silencing increases TNF-related apoptosis-inducing ligand (TRAIL)-R2 (DR5) expression and sensitizes melanoma cells to TRAIL-induced apoptosis. Consistent with the general increase in histone deacetylases, as by the proteomic profile, the immune precipitation assay showed decreased acetyl-Yin Yang 1 (YY1) after FKBP51 depletion, suggesting an impaired repressor activity of this transcription factor. ChIP assay supported this hypothesis. Compared with non-silenced cells, a reduced acetyl-YY1 was found on the DR5 promoter, resulting in increased DR5 transcript levels. Using Crispr/Cas9 knockout (KO) melanoma cells, we confirmed the negative regulation of DR5 by FKBP51. We also show that KO cells displayed reduced levels of acetyl-EP300 responsible for YY1 acetylation, along with reduced acetyl-YY1. Reconstituting FKBP51 levels contrasted the effects of KO on DR5, acetyl-YY1, and acetyl-EP300 levels. In conclusion, our finding shows that FKBP51 reduces DR5 expression at the transcriptional level by promoting YY1 repressor activity. Our study supports the conclusion that targeting FKBP51 increases the expression level of DR5 and sensitivity to TRAIL-induced cell death, which can improve the tumoricidal action of immune cells.
Highlights
Melanoma is insidious cancer that is highly resistant to cytotoxic treatments
Using two different melanoma cell lines and three different methods for FKBP51 modulation, namely short interfering RNA, short hairpin RNA, and CRISPR/Cas9 KO, we show that FKBP51 silencing increased DR5 expression and enhanced sensitivity of melanoma cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis
Because DR5 positively correlates with the overall survival of melanoma patients, we looked at role of FKBP51 in the regulation of DR5 expression in melanoma cells
Summary
Melanoma is insidious cancer that is highly resistant to cytotoxic treatments. This neoplasia is among the most immunogenic tumors and has the highest potential to elicit specific adaptive antitumor immune responses (Passarelli et al, 2017). Among factors regulating melanoma sensitivity to TRAIL, the level of cellsurface expression of specific death receptors (DR), in particular DR5, plays a relevant role in TRAIL response, as suggested by several studies (Zhang et al, 1999; Hersey and Zhang, 2001; Nguyen et al, 2001). For this reason, agents to increase the cell-surface expression of TRAIL-DRs on melanoma cells are expected to improve the clinical efficacy of soluble TRAIL (Chen et al, 2007). Not referred to as a prognostic factor of melanoma, DR5 expression positively correlates with the overall survival of melanoma patients (see text footnote 1)
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