Abstract
Melanoma is the most aggressive skin cancer; there is no cure in advanced stages. Identifying molecular participants in melanoma progression may provide useful diagnostic and therapeutic tools. FK506 binding protein 51 (FKBP51), an immunophilin with a relevant role in developmental stages, is highly expressed in melanoma and correlates with aggressiveness and therapy resistance. We hypothesized a role for FKBP51 in melanoma invasive behaviour. FKBP51 promoted activation of epithelial-to-mesenchymal transition (EMT) genes and improved melanoma cell migration and invasion. In addition, FKBP51 induced some melanoma stem cell (MCSC) genes. Purified MCSCs expressed high EMT genes levels, suggesting that genetic programs of EMT and MCSCs overlap. Immunohistochemistry of samples from patients showed intense FKBP51 nuclear signal and cytoplasmic positivity for the stem cell marker nestin in extravasating melanoma cells and metastatic brains. In addition, FKBP51 targeting by small interfering RNA (siRNA) prevented the massive metastatic substitution of liver and lung in a mouse model of experimental metastasis. The present study provides evidence that the genetic programs of cancer stemness and invasiveness overlap in melanoma, and that FKBP51 plays a pivotal role in sustaining such a program.
Highlights
FK506 binding protein 51 (FKBP51) overexpression was apparently associated with a melanoma cancer stem cell (MCSC) phenotype.8FKBP51 (FKBP5 official symbol) is a large molecular weight component of the family of FK506 binding proteins (FKBPs), classically known as the intracellular receptors for immunosuppressants FK506 and rapamycin.[12,13] FKBPs are multifunctional proteins that modulate several signal transduction pathways.[12,13,14,15] the knowledge of FKBP structure and function is far from complete, recent reports reveal that this class of proteins affects gene expression, DNA repair, and DNA replication
PAS-1 (PASTICCINO1 gene), the FKBP51 homologue in Arabidopsis, plays a critical role in the growth and differentiation of this organism.19Recent breakthroughs suggest that genes active in developmental processes are relevant to cancer biology and play a determinant role in reprogramming cancer cells to activate stemness.[20]
Using Boyden chamber and matrigel,[28] we found that the ability of melanoma cells to migrate through transwell filters and invade matrigel was enhanced by FKBP51-overexpression (Figure 1g)
Summary
FKBP51 overexpression was apparently associated with a melanoma cancer stem cell (MCSC) phenotype.8FKBP51 (FKBP5 official symbol) is a large molecular weight component of the family of FK506 binding proteins (FKBPs), classically known as the intracellular receptors for immunosuppressants FK506 and rapamycin.[12,13] FKBPs are multifunctional proteins that modulate several signal transduction pathways.[12,13,14,15] the knowledge of FKBP structure and function is far from complete, recent reports reveal that this class of proteins affects gene expression, DNA repair, and DNA replication (reviewed in Yao et al.[15]) These functions are mediated by histone chaperone activity, regulation of transcription factors, and modifications of chromatin structure.[15] In accordance with these concepts, FKBP51 plays a relevant role in developmental stages in both mammals[16,17,18] and other organisms.[19] FKBP51 is among the top candidate genes expressed in mesenchymal stem cells,[18] during the mitotically active phase that precedes differentiation into the three mesodermal lineages, namely osteogenesis/chondrogenesis/adipogenesis.[16,17]. We hypothesized a role for FKBP51 in the regulation of the melanoma stemness phenotype and invasive behaviour
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