Abstract
Sodium butyrate (NaBu) and sodium 4‐phenylbutyrate (4PBA) have promising futures in cancer treatment; however, their underlying molecular mechanisms are not clearly understood. Here, we show A549 cell death induced by NaBu and 4PBA are not the same. NaBu treatment induces a significantly higher level of A549 cell death than 4PBA. A gene expression microarray identified more than 5000 transcripts that were altered (>1.5‐fold) in NaBu‐treated A549 cells, but fewer than 2000 transcripts that were altered in 4PBA. Moreover, more than 100 cell cycle‐associated genes were greatly repressed by NaBu, but slightly repressed by 4PBA; few genes were significantly upregulated only in 4PBA‐treated cells. Gene expression was further validated by other experiments. Additionally, A549 cells that were treated with these showed changes in glucose consumption, caspase 3/7 activation and histone modifications, as well as enhanced mitochondrial superoxide production. TXNIP was strongly induced by NaBu (30‐ to 40‐fold mRNA) but was only slightly induced by 4PBA (two to fivefold) in A549 cells. TXNIP knockdown by shRNA in A549 cells significantly attenuated caspase 3/7 activation and restored cell viability, while TXNIP overexpression significantly increased caspase 3/7 activation and cell death only in NaBu‐treated cells. Moreover, TXNIP also regulated NaBu‐ but not 4PBA‐induced H4K5 acetylation and H3K4 trimethylation, possibly by increasing WDR5 expression. Finally, we demonstrated that 4PBA induced a mitochondrial superoxide‐associated cell death, while NaBu did so mainly through a TXNIP‐mediated pathway. The above data might benefit the future clinic application.
Highlights
Histone post-translational modification is one of the epigenetic mechanisms controlling longevity and the development of various diseases, including tumors, in diverse organisms [1, 2]
We treated A549 cells with 5 mmol/L NaBu, or 5 mmol/L 4PBA for 72 h and stained them with DAPI, a nuclear, specific fluorescence dye. We found that both inhibitors can significantly prevent A549 cell proliferation and promote cell death; NaBu-treated A549 cells showed a lower proliferation and cell viability compared to those of 4PBA-treated cells (Fig. 1A)
The results showed that both NaBu and 4PBA could enhance the total histone acetylation, histone H4 lysine 5 acetylation, histone H3 lysine 9 acetylation, histone H3 lysine 18 acetylation and histone H3 lysine 4 trimethylation (H3K4me3), but histone
Summary
Histone post-translational modification is one of the epigenetic mechanisms controlling longevity and the development of various diseases, including tumors, in diverse organisms [1, 2]. Histone protein acetylation and methylation are dynamic processes that change DNA accessibility and regulate gene expression by influencing chromatin structure [1, 2]. Several types of acetylated histones, such as histone H3 lysine 9 (acH3K9), histone H4 lysine 5 (acH4K5) and histone H3 lysine 18 (acH3K18), have been identified, and their roles in different cellular processes have been gradually determined [3]. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are responsible for the balance of histone acetylation modification with physiological status. Different lysine sites undergoing methylation correlate with either transcriptional activation, such as H3K4 [4], or transcriptional repression, such as H3K9 and H3K27 [5]. Histone methylation might promote DNA methylation, causing the further repression of the affected genes [1, 2]. Lysine 4 of histone H3 is primarily methylated by the lysine (K)-specific
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