Abstract:BackgroundDefects in the type and degree of cellular glycosylation impact oncogenesis on multiple levels. Although the type of glycosylation is determined by protein sequence encoded by the genome, the extent and modifications of glycosylation depends on the activity of biosynthetic enzymes and recent data suggests that the glycome is also subject to epigenetic regulation. This study focuses on the ability of HDAC inhibition to alter glycosylation and to lead to pro-oncogenic alterations in the glycome as asse… Show more
“…6 C). These findings are consistent with previous research demonstrating that BCL2 is overexpressed during EMT [ 24 , 25 ], and provides insight into previously observed chemotherapeutic resistance in SW13+ cells [ 18 ]. Fig.…”
Section: Resultssupporting
confidence: 92%
“…[ 16 ]. However, while HDAC inhibitors induce toxicity and slow cell growth in some cell types, they can also increase metastatic properties and chemotherapy resistance in others [ 17 , 18 ]. As iron is also critical for tumor cell growth, we examined whether manipulation of intracellular iron availability could improve HDAC inhibitor treatment outcomes.…”
Epithelial-to-mesenchymal transition (EMT) is an essential mechanism for development and wound healing, but in cancer it also mediates the progression and spread of aggressive tumors while increasing therapeutic resistance. Adoption of a mesenchymal state is also associated with increased iron uptake, but the relationship between EMT and the key regulators of cellular iron metabolism remains undefined. In this regard, the human adrenal cortical carcinoma SW13 cell line represents an invaluable research model as HDAC inhibitor treatment can convert them from an epithelial-like (SW13-) cell type to a mesenchymal-like (SW13+) subtype. In this study we establish SW13 cells as a model for exploring the link between iron and EMT. Increased iron accumulation following HDAC inhibitor mediated EMT is associated with decreased expression of the iron export protein ferroportin, enhanced ROS production, and reduced expression of antioxidant response genes. As availability of redox active iron and loss of lipid peroxide repair capacity are hallmarks of ferroptosis, a form of iron-mediated cell death, we next examined whether HDAC inhibitor treatment could augment ferroptosis sensitivity. Indeed, HDAC inhibitor treatment synergistically increased cell death following induction of ferroptosis. The exact mechanisms by which HDAC inhibition facilitates cell death following ferroptosis induction requires further study. As several HDAC inhibitors are already in use clinically for the treatment of certain cancer types, the findings from these studies have immediate implications for improving iron-targeted chemotherapeutic strategies.
“…6 C). These findings are consistent with previous research demonstrating that BCL2 is overexpressed during EMT [ 24 , 25 ], and provides insight into previously observed chemotherapeutic resistance in SW13+ cells [ 18 ]. Fig.…”
Section: Resultssupporting
confidence: 92%
“…[ 16 ]. However, while HDAC inhibitors induce toxicity and slow cell growth in some cell types, they can also increase metastatic properties and chemotherapy resistance in others [ 17 , 18 ]. As iron is also critical for tumor cell growth, we examined whether manipulation of intracellular iron availability could improve HDAC inhibitor treatment outcomes.…”
Epithelial-to-mesenchymal transition (EMT) is an essential mechanism for development and wound healing, but in cancer it also mediates the progression and spread of aggressive tumors while increasing therapeutic resistance. Adoption of a mesenchymal state is also associated with increased iron uptake, but the relationship between EMT and the key regulators of cellular iron metabolism remains undefined. In this regard, the human adrenal cortical carcinoma SW13 cell line represents an invaluable research model as HDAC inhibitor treatment can convert them from an epithelial-like (SW13-) cell type to a mesenchymal-like (SW13+) subtype. In this study we establish SW13 cells as a model for exploring the link between iron and EMT. Increased iron accumulation following HDAC inhibitor mediated EMT is associated with decreased expression of the iron export protein ferroportin, enhanced ROS production, and reduced expression of antioxidant response genes. As availability of redox active iron and loss of lipid peroxide repair capacity are hallmarks of ferroptosis, a form of iron-mediated cell death, we next examined whether HDAC inhibitor treatment could augment ferroptosis sensitivity. Indeed, HDAC inhibitor treatment synergistically increased cell death following induction of ferroptosis. The exact mechanisms by which HDAC inhibition facilitates cell death following ferroptosis induction requires further study. As several HDAC inhibitors are already in use clinically for the treatment of certain cancer types, the findings from these studies have immediate implications for improving iron-targeted chemotherapeutic strategies.
“…In particular, HDACs are related to repression of genes that encode proteins involved in tumorigenesis, specifically in control of cell growth, differentiation and apoptosis [ 7 ]. The association of HDACs with glycosylation patterns has been reported for cancer indications such as neuroblastoma and adrenocortical carcinoma [ 8 , 9 ].…”
“…Moreover, we previously found that DR5 is activated by fucosylation for TRAIL-induced apoptosis using our TRAIL variants [47]. Interestingly, recently a relation between HDAC inhibition and glycosylation pattern was reported which can hint at an explanation for increasing sensitivity of TRAIL receptors in the presence of HDAC inhibitors [48]. In our current study, we investigated the expression of DR4 and DR5 on the cell membrane and our results show significant DR4 but not DR5 expression enhancement on DLD-1 cells, while DR5 but not DR4 expression is increased on WiDr cells.…”
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered as a promising anti-cancer therapeutic. However, many cancers have been found to be or to become inherently resistant to TRAIL. A combination of epigenetic modifiers, such as histone deacetylase inhibitors (HDACi’s), with TRAIL was effective to overcome TRAIL resistance in some cancers. Broad spectrum HDACi’s, however, show considerable toxicity constraining clinical use. Since overexpression of class I histone deacetylase (HDAC) has been found in colon tumors relative to normal mucosa, we have focused on small spectrum HDACi’s. We have now tested agonistic receptor-specific TRAIL variants rhTRAIL 4C7 and DHER in combination with several class I specific HDACi’s on TRAIL-resistant colon cancer cells DLD-1 and WiDr. Our data show that TRAIL-mediated apoptosis is largely improved in WiDr cells by pre-incubation with Entinostat-a HDAC1, 2, and 3 inhibitor- and in DLD-1 cells by RGFP966-a HDAC3-specific inhibitor- or PCI34051-a HDAC8-specific inhibitor. We are the first to report that using RGFP966 or PCI34051 in combination with rhTRAIL 4C7 or DHER represents an effective cancer therapy. The intricate relation of HDACs and TRAIL-induced apoptosis was confirmed in cells by knockdown of HDAC1, 2, or 3 gene expression, which showed more early apoptotic cells upon adding rhTRAIL 4C7 or DHER. We observed that RGFP966 and PCI34051 increased DR4 expression after incubation on DLD-1 cells, while RGFP966 induced more DR5 expression on WiDr cells, indicating a different role for DR4 or DR5 in these combinations. At last, we show that combined treatment of RGFP966 with TRAIL variants (rhTRAIL 4C7/DHER) increases apoptosis on 3D tumor spheroid models.
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