FOXA1 Regulation Turns Benzamide HDACi Treatment Effect-Specific in BC, Promoting NIS Gene-Mediated Targeted Radioiodine Therapy

Abstract

Human sodium iodide symporter ( NIS ) gene mediated radio-ablation is a successful procedure in thyroid cancer clinics. In recent years, natural expression of NIS is reported in breast cancer (BC) cases but is yet to make its mark as a therapeutic procedure in BC clinics. A pre-exposure to histone deacetylase (HDAC) inhibitors to amplify endogenous NIS expression was attempted, but achieving cancer tissue-specific enhancement of NIS in patients is an important challenge to win. Here, for the first time, we show that a benzamide class of HDACi (bHDACi) can significantly induce NIS gene expression and function (p < 0.05) in BC cells with minimal off-target effects. Transcription factor (TF) profiler and promoter binding array reveals 22 TFs differentially activated by CI-994, of which FOXA1 is identified as a unique and positive regulator of NIS. Clonogenic assay shows reduced survival with bHDACi + 131 I combination treatment. Further, AR-42 and MS-275 treatment shows enhanced NIS expression in an orthotopic breast tumor model. Combining bHDACi with 1 mCi 131 I shows 40% drop in signal (p < 0.05), indicating enhanced radio-ablation effect. Cerenkov imaging revealed higher accumulation of 131 I in MS-275-treated tumors. Thus, bHDACi-mediated selective enhancement ensuring minimal off-target effect is a step further toward using NIS as a therapeutic target for BC.

Cross-talk between the gut microbiota and hypothyroidism: a bidirectional two-sample Mendelian randomization study

“…SCFAs play a crucial role in the regulation of sodium/iodine symporter (NIS) expression in thyroid cells. Previous research has demonstrated that SCFA, particularly butyric acid, inhibits histone deacetylase (HDAC) and activates NIS re-expression in thyroid cancer cells, leading to redifferentiation and enhanced iodine uptake ( 73 ). Additionally, SCFAs like butyrate and propionate have been found to preserve the integrity of the intestinal barrier by influencing the expression of MUC2 mRNA levels ( 74 ).…”

“…SCFA-producing bacteria such as Akkermansia, Butyrivibrio, Holdemania, Anaerostipes, and Intestinimonas were identified in this study as part of the gut microbiota associated with hypothyroidism. SCFAs play a crucial role in the regulation of sodium/iodine symporter (NIS) expression in (73). Additionally, SCFAs like butyrate and propionate have been found to preserve the integrity of the intestinal barrier by influencing the expression of MUC2 mRNA levels (74).…”

Causal analysis of the gut microbiota in differentiated thyroid carcinoma: a two-sample Mendelian randomization study

“…Interestingly, it has also been identified as a potential etiological factor contributing to Graves’ Disease (GD) ( Cao et al, 2023 ). This association may be attributed to the ability of short-chain fatty acids (SCFA) to inhibit histone deacetylases (HDAC) and activate the re-expression of transport proteins in thyroid cancer cells, thereby inducing the differentiation of tumor cells and enhancing iodine uptake ( Zhou et al, 2018 ; Rathod et al, 2020 ). Genus Paraprevotella has been the subject of several studies.…”

The relationships between the gut microbiota and its metabolites with thyroid diseases

“…Similarly, SCFAs, an important metabolite of the intestinal microbiota, are also important in regulating NIS expression in thyroid cells. It is well established that SCFAs, especially butyric acid, can inhibit histone deacetylase (HDAC) and activate NIS re-expression in thyroid cancer cells, thereby inducing re-differentiation and iodine uptake ( 37 , 38 ). This phenomenon, interestingly, was not limited to thyroid cancer cell lines, as consistent results were observed in other tumor cell lines such as MCF-7, Hep-G2, and MKN-7 ( 37 , 38 ).…”

“…It is well established that SCFAs, especially butyric acid, can inhibit histone deacetylase (HDAC) and activate NIS re-expression in thyroid cancer cells, thereby inducing re-differentiation and iodine uptake ( 37 , 38 ). This phenomenon, interestingly, was not limited to thyroid cancer cell lines, as consistent results were observed in other tumor cell lines such as MCF-7, Hep-G2, and MKN-7 ( 37 , 38 ). Thus, it is envisaged that the sensitivity of tumor cells to radioactive iodine uptake could be increased by modulating the SCFAs to promote histone acetylation and enhance NIS expression, though further investigations are yet needed.…”