Transcriptional regulation of ABC drug transporters

Scotto, Kathleen W.

doi:10.1038/sj.onc.1206950

Cited by 356 publications

(278 citation statements)

References 125 publications

Supporting

Mentioning

261

Contrasting

Unclassified

Order By: Relevance

“…Epigenetic mechanisms (histone acetylation, DNA methylation) have been shown to play a pivotal role in ABCB1 gene expression in several tumour cell systems (El-Osta et al, 2002;Labialle et al, 2002;Scotto, 2003).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model

et al. 2007

View full text Add to dashboard Cite

Tumour drug-resistant ABCB1 gene expression is regulated at the chromatin level through epigenetic mechanisms. We examined the effects of the histone deacetylase inhibitor trichostatin A (TSA) on ABCB1 gene expression in small cell lung carcinoma (SCLC) drugsensitive (H69WT) or etoposide-resistant (H69VP) cells. We found that TSA induced an increase in ABCB1 expression in drugsensitive cells, but strongly decreased it in drug-resistant cells. These up-and downregulations occurred at the transcriptional level. Protein synthesis inhibition reduced these modulations, but did not completely suppress them. Differential temporal patterns of histone acetylation were observed at the ABCB1 promoter: increase in H4 acetylation in both cell lines, but different H3 acetylation with a progressive increase in H69WT cells but a transient one in H69VP cells. ABCB1 regulations were not related with the methylation status of the promoter À50GC, À110GC, and Inr sites, and did not result in further changes to these methylation profiles. Trichostatin A treatment did not modify MBD1 binding to the ABCB1 promoter and similarly increased PCAF binding in both H69 cell lines. Our results suggest that in H69 drug-resistant SCLC cell line TSA induces downregulation of ABCB1 expression through a transcriptional mechanism, independently of promoter methylation, and MBD1 or PCAF recruitment.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Considerable progress has been made towards the definition of the regulatory mechanisms that control the expression of ABCB1 gene in tumour cells (for review, see Labialle et al, 2002;Scotto, 2003). The ABCB1 promoter lacks a TATA box and contains an initiator element (Inr) necessary for its transcription.…”

mentioning

confidence: 99%

The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Professional lipid ABC transporters, such as the cholesterol and phospholipid transporter ABCA1, the long-chain PC and cholesterol transporter ABCB4 (MDR3), the bile salt transporter ABCB11 (BSEP/S-P-gp), or the major sterol transporters ABCG5/G8 (working as an obligate heterodimer), have indeed been shown to be regulated by lipid-sensing NRs (Beyea et al, 2007;Jonker et al, 2009;Schmitz & Langmann, 2005;Tarling et al, 2013;van Meer et al, 2008). Interestingly, to date, several NRs also involved in the recognition of lipid ligands have been shown to affect the gene expression of human ABCB1 and ABCG2, the transport functions of which are mainly involved in causing multidrug resistance (Borst & Elferink, 2002;Jonker et al, 2009;Klaassen & Aleksunes, 2010;Natarajan, Xie, Baer, & Ross, 2012;Sarkadi et al, 2006;Scotto, 2003). Therefore, via binding to and activating their cognate NRs, lipid molecules might also be directly involved in the transcriptional regulation of both ABCB1 and ABCG2.…”

Section: P0280mentioning

confidence: 99%

Lipid Regulation of the ABCB1 and ABCG2 Multidrug Transporters

Hegedüs

Telbisz

Hegedüs

et al. 2015

Advances in Cancer Research

View full text Add to dashboard Cite

“…The regulation of the MDR1 gene transcription also requires involvement of a number of transcriptional factors and co-regulators, including HIF-1, p53, NF-Y, c-fos, c-jun, NF-kB, etc. (9,10). The elucidation of the roles of these factors in MDR1 gene transcription has led to a better understanding of the regulation of the expression of this gene, and helped develop new strategies to inhibit or prevent the induction of MDR1 expression.…”

Section: Introductionmentioning

confidence: 99%

Involvement of CtBP1 in the transcriptional activation of the MDR1 gene in human multidrug resistant cancer cells

Jin

Scotto

Hait

et al. 2007

Biochemical Pharmacology

View full text Add to dashboard Cite

Drug resistance caused by overexpression of P-glycoprotein (P-gp), the MDR1 (ABCB1) gene product, limits the therapeutic outcome. Expression of MDR1 can be induced by divergent stimuli, and involves a number of transcriptional factors. We found that the expression of CtBP1 (C-terminalbinding protein 1), a transcriptional co-regulator, was increased (~4 -fold) in human multidrug resistant (MDR) cancer cell lines, NCI/ADR-RES and A2780/DX, as compared to their sensitive counterparts. Silencing of CtBP1 expression by RNAi decreased the MDR1 mRNA and P-gp. Knockdown of CtBP1 also enhanced the sensitivity of MDR cells to chemotherapeutic drugs that are transported by P-gp and increased intracellular drug accumulation. In a reporter gene assay, cotransfection of MDR1 promoter constructs with a CtBP1 expression vector resulted in a ~2-4-fold induction of MDR1 promoter activity. CtBP1 appeared to contribute to the activation of MDR1 transcription through directly interacting with the MDR1 promoter, as evidenced by its physical binding to the promoter region of the MDR1 gene in chromatin immunoprecipitation and electromobility shift assays. Histone modifications at the MDR1 promoter, such as monomethylation, di-methylation, and acetylation of histone H3, were not found to be affected by silencing of CtBP1 expression. Our results reveal a novel role for CtBP1 as an activator of MDR1 gene transcription, and suggest that CtBP1 might be one of the key transcription factors involved in the induction of MDR1 gene. Therefore, CtBP1 may represent a potentially new target for inhibiting drug resistance mediated by overexpression of the MDR1 gene.

show abstract

Transcriptional regulation of ABC drug transporters

Cited by 356 publications

References 125 publications

The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model

The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model

Lipid Regulation of the ABCB1 and ABCG2 Multidrug Transporters

Involvement of CtBP1 in the transcriptional activation of the MDR1 gene in human multidrug resistant cancer cells

Contact Info

Product

Resources

About