ABSTRACT
BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive type of cancer without any approved targeted therapy. Epigenetic processes have a pivotal role in cancer cell progression and while histone deacetylase 8 (HDAC8) has been proven as a potential oncogene in breast cancer, its underlying molecular mechanism is not known. Therefore, the present study, aimed to evaluate the underlying mechanism of the HDAC8 carcinogenesis in breast cancer progression. METHODS: The potential role of HDAC8 in cancer cell processes such as apoptosis, invasion, migration, angiogenesis, and cancer stem cells (CSCs) markers were evaluated by using flow cytometry Annexin V-FITC/propidium iodide (PI), reverse transcription-polymerase chain reaction (RT-qPCR), Matrigel-coated transwell plates and wound healing assay on both cell lines. The impact of HDAC8 on tumor development was also studied using a breast cancer xenograft model. RESULTS: HDAC8 expression was significantly downregulated in the cell lines, post-transfection with KO-vector. Downregulation of HDAC8 dramatically decreased cell migration, angiogenesis, and invasion while inducing apoptosis in MDAMB-468 and MDA-MB-231 cell lines. HDAC8 knocked out TNBC cell lines had lower levels of cancer stemness markers, such as prominin-1 (CD133), CD44, BMI1, and Aldehyde dehydrogenase 1 (ALDH1). Additionally, the knockout of HDAC8 inhibited tumor growth in a breast cancer xenograft model. CONCLUSION: The findings show that knocking out HDAC8 retains several anticancer actions in BC cells, such as inducing apoptosis, reducing migration, invasion, angiogenesis and removing CSCs markers.
Subject(s)
Triple Negative Breast Neoplasms , Humans , Triple Negative Breast Neoplasms/pathology , Cell Line, Tumor , Gene Deletion , Histone Deacetylases/genetics , Histone Deacetylases/metabolism , Neoplastic Stem Cells/metabolism , Repressor Proteins/geneticsABSTRACT
Recent studies have shown that the histone deacetylase-8 (HDAC8), as one of the HDACs, regulates the expression and activity of various genes involved in cancer initiation and progression. The HDAC8 plays an epigenetic role to dysregulate expressions or to interact with transcription factors. Most researchers had focused on the HDAC 1-3 and 6, but today the HDAC8 isotype is a promising target in cancer therapy. Different studies, on breast cancer (BC) cells, have recently shown the HDAC8 overexpression and suggested its oncogenic potential. It seems that the HDAC8 could be a novel and promising target in breast cancer treatment. Some studies on BC demonstrated therapeutic properties of the inhibitors of HDAC8 such as suberoylanilide hydroxamic acid (SAHA), Trichostatin A, valproic acid, sodium butyrate, 1,3,4 oxadiazole with alanine hybrid [(R)-2-amino-N-((5-phenyl-1,3,4-oxadiazol-2-yl) methyl) propanamide (10b)], N-(2-Hydroxyphenyl)-2propylpentanamide (compound 2) and PCI-34051. In this review, we highlight the role and existing inhibitors of HDAC8 in BC pathogenesis and therapy.
Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/enzymology , Histone Deacetylases/metabolism , Repressor Proteins/metabolism , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/antagonists & inhibitors , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Epigenesis, Genetic , Female , Gene Expression Regulation, Neoplastic , Histone Deacetylase Inhibitors/therapeutic use , Humans , Repressor Proteins/antagonists & inhibitorsABSTRACT
Recent studies show that cancer cells are sometimes able to evade the host immunity in the tumor microenvironment. Cancer cells can express high levels of immune inhibitory signaling proteins. One of the most critical checkpoint pathways in this system is a tumor-induced immune suppression (immune checkpoint) mediated by the programmed cell death protein 1 (PD-1) and its ligand, programmed death ligand 1 (PD-L1). PD-1 is highly expressed by activated T cells, B cells, dendritic cells, and natural killer cells, whereas PD-L1 is expressed on several types of tumor cells. Many studies have shown that blocking the interaction between PD-1 and PD-L1 enhances the T-cell response and mediates antitumor activity. In this review, we highlight a brief overview of the molecular and biochemical events that are regulated by the PD-1 and PD-L1 interaction in various cancers.
