Epigenetic Regulation of Organic Anion Transporting Polypeptide 1B3 in Cancer Cell Lines

Imai, Satoki; Kikuchi, Ryota; Tsuruya, Yuri; Naoi, Sotaro; Nishida, Sho; Kusuhara, Hiroyuki; Sugiyama, Yuichi

doi:10.1007/s11095-013-1117-1

Cited by 43 publications

(42 citation statements)

References 32 publications

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“…Similarly, Nagai et al reported that lung, colon, and pancreatic cancer tissues and cell lines express an alternative OATP1B3 transcript (72). However, this study proposed the four potential ORFs resulting in much shorter amino acid sequences than the ORF reported by our laboratory and another subsequent report (71,100). Currently, csOATP1B3 is found to be the major isoform expressed only in cancer cells, but not in normal tissues.…”

Section: Oatp1b3 (Gene Symbol Slco1b3)mentioning

confidence: 49%

“…With regard to the regulatory mechanisms for OATP1B3 expression, several investigations implicated the involvement of the liver-enriched transcription factor, hepatocyte nuclear factor 3β (HNF3β), as well as epigenetic and hypoxiamediated mechanisms (41,(100)(101)(102). The contribution of these reported mechanisms may vary depending on the tissue types and disease states.…”

Section: Oatp1b3 (Gene Symbol Slco1b3)mentioning

confidence: 99%

“…A later study showed that epigenetic mechanisms by DNA methylation-dependent gene silencing are involved in the regulation of OATP1B3 in different cancer cell lines (101). A more recent study showed that DNA methylation-dependent gene silencing involving methyl-DNA binding protein 2 (MBD2) regulates the expression of csOATP1B3 (100). A study by Han et al showed that csOATP1B3, but not OATP1B3 WT, is transcriptionally activated by hypoxia (102).…”

Section: Oatp1b3 (Gene Symbol Slco1b3)mentioning

confidence: 99%

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Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy

Thakkar

Lockhart

Lee

2015

AAPS J

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Abstract. The superfamily of organic anion-transporting polypeptides (OATPs, gene symbol SLCO) includes important transporters handling a variety of endogenous and xenobiotic substrates. Currently, 11 human OATPs are known and their substrates include endogenous hormones and their conjugates, anticancer drugs, and imaging agents. The contribution of OATPs to the in vivo disposition of these substrates has been extensively investigated. An accumulating body of evidence also indicates that the expression of some OATPs may be up-or downregulated in several types of cancers, suggesting potential pathogenic roles during the development and progression of cancer. Given that the role of OATPs in handling cancer therapeutics has been already covered by several excellent reviews, this review will focus on the recent progresses on the topic, in particular the role of OATPs in the disposition of anticancer drugs, the impact of OATP genetic variations on the function of OATPs, and the OATPs differentially expressed in cancer and their potential roles in cancer development, progression, and treatment.

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Section: Oatp1b3 (Gene Symbol Slco1b3)mentioning

confidence: 49%

Section: Oatp1b3 (Gene Symbol Slco1b3)mentioning

confidence: 99%

Section: Oatp1b3 (Gene Symbol Slco1b3)mentioning

confidence: 99%

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Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy

Thakkar

Lockhart

Lee

2015

AAPS J

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“…3) Development stage-dependent CYP2E1 expression is influenced by the methylation status of this gene. 4) Phase II genes including UGT1A1 , GSTP1 , SULT1A1 and genes for efflux transporters like MDR1, BCRP and members of the OATP family of uptake transporters are epigenetically regulated due to DNA methylation [86, 87, 89, 88]. …”

Section: Genetics Epigenetics and Interindividual Differences In Dmentioning

confidence: 99%

Nuclear Receptors in Drug Metabolism, Drug Response and Drug Interactions

Prakash

Zuniga

Song

et al. 2015

Nuclear Receptor Research

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Orally delivered small-molecule therapeutics are metabolized in the liver and intestine by phase I and phase II drug-metabolizing enzymes (DMEs), and transport proteins coordinate drug influx (phase 0) and drug/drug-metabolite efflux (phase III). Genes involved in drug metabolism and disposition are induced by xenobiotic-activated nuclear receptors (NRs), i.e. PXR (pregnane X receptor) and CAR (constitutive androstane receptor), and by the 1α, 25-dihydroxy vitamin D3-activated vitamin D receptor (VDR), due to transactivation of xenobiotic-response elements (XREs) present in phase 0-III genes. Additional NRs, like HNF4-α, FXR, LXR-α play important roles in drug metabolism in certain settings, such as in relation to cholesterol and bile acid metabolism. The phase I enzymes CYP3A4/A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, CYP1A2, CYP2C8, CYP2A6, CYP2J2, and CYP2E1 metabolize >90% of all prescription drugs, and phase II conjugation of hydrophilic functional groups (with/without phase I modification) facilitates drug clearance. The conjugation step is mediated by broad-specificity transferases like UGTs, SULTs, GSTs. This review delves into our current understanding of PXR/CAR/VDR-mediated regulation of DME and transporter expression, as well as effects of single nucleotide polymorphism (SNP) and epigenome (specified by promoter methylation, histone modification, microRNAs, long non coding RNAs) on the expression of PXR/CAR/VDR and phase 0-III mediators, and their impacts on variable drug response. Therapeutic agents that target epigenetic regulation and the molecular basis and consequences (overdosing, underdosing, or beneficial outcome) of drug-drug/drug-food/drug-herb interactions are also discussed. Precision medicine requires understanding of a drug’s impact on DME and transporter activity and their NR-regulated expression in order to achieve optimal drug efficacy without adverse drug reactions. In future drug screening, new tools such as humanized mouse models and microfluidic organs-on-chips, which mimic the physiology of a multicellular environment, will likely replace the current cell-based workflow.

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“…Several studies have shown that this gene is ectopically expressed in solid tumors of non-hepatic origin, particularly colon cancer [131–134]. Investigations into the cause of this ectopic expression revealed that the normal liver-restricted promoter is silent in these cancers, with expression of “cancer-type” (Ct)-OATP1B3 being driven from an alternative promoter in the second canonical intron [133, 134]. While not previously reported as being within a TE, we noted that this alternative promoter maps within the 5’ LTR (LTR7) of a partly full-length antisense HERV-H element that is missing the 3’ LTR.…”

Section: Introductionmentioning

confidence: 99%

Endogenous retroviral promoter exaptation in human cancer

2016

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Cancer arises from a series of genetic and epigenetic changes, which result in abnormal expression or mutational activation of oncogenes, as well as suppression/inactivation of tumor suppressor genes. Aberrant expression of coding genes or long non-coding RNAs (lncRNAs) with oncogenic properties can be caused by translocations, gene amplifications, point mutations or other less characterized mechanisms. One such mechanism is the inappropriate usage of normally dormant, tissue-restricted or cryptic enhancers or promoters that serve to drive oncogenic gene expression. Dispersed across the human genome, endogenous retroviruses (ERVs) provide an enormous reservoir of autonomous gene regulatory modules, some of which have been co-opted by the host during evolution to play important roles in normal regulation of genes and gene networks. This review focuses on the “dark side” of such ERV regulatory capacity. Specifically, we discuss a growing number of examples of normally dormant or epigenetically repressed ERVs that have been harnessed to drive oncogenes in human cancer, a process we term onco-exaptation, and we propose potential mechanisms that may underlie this phenomenon.

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Epigenetic Regulation of Organic Anion Transporting Polypeptide 1B3 in Cancer Cell Lines

Abstract: Ct-OATP1B3 is capable of transporting its substrates into cancer cells. Its mRNA expression is regulated by DNA methylation-dependent gene silencing involving MBD2.

Cited by 43 publications

References 32 publications

Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy

Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy

Nuclear Receptors in Drug Metabolism, Drug Response and Drug Interactions

Endogenous retroviral promoter exaptation in human cancer

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