title: TXNIP mediates the differential responses of A549 cells to sodium butyrate and sodium 4-phenylbutyrate treatment.
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.
authors.affiliation: School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
authors.forename: Xuefang
authors.initials: X
authors.lastname: Jin
authors.affiliation: The Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, China.
authors.forename: Nana
authors.initials: N
authors.lastname: Wu
authors.affiliation: Department of General Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, China.
authors.forename: Juji
authors.initials: J
authors.lastname: Dai
authors.affiliation: The Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, China.
authors.forename: Qiuxia
authors.initials: Q
authors.lastname: Li
authors.affiliation: The Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, China.|Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China.
authors.forename: XiaoQiang
authors.initials: X
authors.lastname: Xiao
mesh_terms: D000072283:A549 Cells; D020148:Butyric Acid / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010654:Phenylbutyrates / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D010654:Phenylbutyrates; C486715:TXNIP protein, human; D020148:Butyric Acid; C075773:4-phenylbutyric acid; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D005947:Glucose
keywords: A549 cells; TXNIP; butyrate; histone modification; mitochondrial superoxide