HDAC inhibition induces EMT and alterations in cellular iron homeostasis to augment ferroptosis sensitivity in SW13 cells

Abstract

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.

Sumoylated SnoN interacts with HDAC1 and p300/CBP to regulate EMT in mammary organoids

“…HDAC1 acts with distinct transcription factors to regulate the abundance of mRNA encoding Ecadherin to promote or suppress EMT [41][42][43] . Interestingly, incubation of human adrenal cortical carcinoma cells with a class I HDAC inhibitor promotes EMT in these cells, supporting the idea that HDAC1 may act as a suppressor of EMT 44 . That HDAC1 suppresses EMT in a deacetylase-dependent manner, uncovered in the current study, is further supported by our nding that the histone acetylase p300 promotes EMT in epithelial and carcinoma organoids.…”

Soft Tissue Sarcoma Study: Association of Genetic Alterations in the Apoptosis Pathways with Chemoresistance to Doxorubicin

“…H193Y mutation in the DNA-binding domain of TP53, revealed in specimen AF53b, according to Clarke et al, is associated with lower mRNA expression of CDKN1A and protein expression of Fdxr [ 34 ]. Moreover, Oliveira et al refer this mutation to abnormalities associated with gain-of-function and leading to TP53 accumulation [ 35 ]. Accumulation of the mutated TP53 in the case of gain-of-function mutations do not ensure the high transcriptional activity similar to wild type protein but lead to the activation of different signaling pathways [ 32 ].…”

Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer

“…HDAC inhibitor romidepsin (also called FK228) affects iron metabolism, mediates increased intracellular iron accumulation, decreases the expression of export-type ferroprotein, and increases reactive oxygen species (ROS) production, thereby, mediating iron death. This result has a guiding role for the combined treatment strategy using HDAC inhibitors and iron-targeted chemotherapy (Oliveira et al, 2021). The results of the second-phase clinical study show that FK228 can effectively control T-cell lymphoma, with safety and reliability (NCT00426764, NCT00106431) (Table 2) (Foss et al, 2014;Foss et al, 2016).…”