ABCB1 Promoter Methylation: A Potential Biomarker and Therapeutic Target in the Pathogenesis of Ulcerative Colitis
Document Type : Original Article
Authors
1 MSc Student, Department of Pathobiology, Faculty of Veterinary Medicine, Bu-Ali Sina University, Hamedan, Iran
2 Department of Pathobiology, Faculty of Veterinary Medicine, Bu-Ali Sina University, Hamedan, Iran
Abstract
The aim of this systematic review was to synthesize the existing evidence on the role of ABCB1 promoter methylation in the pathogenesis of ulcerative colitis (UC) and to evaluate its potential as a biomarker and therapeutic target. A systematic search was conducted across PubMed/MEDLINE, Scopus, Embase, Web of Science, and the Cochrane Library for articles published up to March 2024. Original human, animal, and cellular studies examining the association between ABCB1 methylation and UC were selected based on predetermined criteria, and their quality was assessed using standard tools. A total of 38 studies met the inclusion criteria. The evidence consistently indicated that ABCB1 promoter methylation levels in the colonic tissue of UC patients were signi cantly higher than in healthy individuals. A signi cantinverse correlation between increased methylation levels and decreased expression of ABCB1 mRNA and Pglycoprotein was reported in most studies. Furthermore, ABCB1 hypermethylation was associated with increased disease severity, a higher risk of relapse, and a poorer response to standard treatments. Laboratory studies demonstrated that pharmacological interventions and natural compounds could reverse this epigenetic alteration. Therefore, it can be concluded that ABCB1 promoter hypermethylation is an important epigenetic event in UC pathogenesis, contributing to intestinal barrier dysfunction and in ammation by silencing a key protective gene. This marker has high potential for application in the diagnosis, prognosis, and personalized treatment of UC.
Keywords
References
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to mechanism. Oncogene. 2003;22(47):7468-85.
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amed human intestinal epithelium is indepen-
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2019;10(12):7965-76.
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moter hypermethylation of the ABCB1 gene is a
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ative colitis and its relationship with the risk of
colorectal cancer. Mol Med Rep. 2016;14(5):4557-
63.
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ammatory bowel disease. World J Gastroenterol.
2010;16(27):3371-7.
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Genet Dev. 1996;6(5):610-7.
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methylome map of ulcerative colitis. Genome Res.
2012;22(11):2130-7.
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Leenaars M, Ritskes-Hoitinga M, Langendam
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S, Ota T, Kajimoto K, et al. Mesalamine in-
hibits DNA methyltransferase and restores P-
glycoprotein expression in Caco-2 cells. Biochem
Biophys Res Commun. 2018;499(3):477-82.
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Rev Genet. 2012;13(7):484-92.
[14] Kaplan GG, Ng SC. Understanding and prevent-
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origins of in ammatory bowel diseases. Can J Gas-
troenterol. 2012;26(12):909-15.16. Langmann T,
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V, Gregor M, et al. Gene expression of the tran-
scriptional coactivator PGC-1alpha is decreased in
experimental and human in ammatory bowel dis-
ease. Gut. 2004;53(11):1644-51.
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van der Woude CJ. IL-6-induced DNMT1 ac-
tivity mediates SOCS3 promoter hypermethyla-
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model of colitis-associated cancer. J Ethnophar-
macol. 2020;253:112653.
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tients with ulcerative colitis. J Clin Biochem Nutr.
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ABCB1 Promoter Methylation: A Potential Biomarker ...: 31{37 36
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W, Benchimol EI, et al. Worldwide incidence and
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model of in ammatory bowel disease: mice de-
cient for the multiple drug resistance gene,
mdr1a, spontaneously develop colitis. J Immunol.
1998;161(10):5733-44.
[21] Sadeghi H, Zare-Bidaki M, Zivari-Rahman M,
Kazemi-Nia AR, Fakhari H. High frequency of
ABCB1 promoter methylation in ulcerative col-
itis patients. Gastroenterol Hepatol Bed Bench.
2020;13(4):341-7.24. Schmidt C, Gaser C, Kret-
zschmar V, Schrmann S, Brckner S, Gerlach U,
et al. DNA methylation of the ABCB1 promoter
is a predictive biomarker for response to gluco-
corticoids in ulcerative colitis. Clin Epigenetics.
2018;10:19.
[22] Tahara T, Shibata T, Nakamura M, Yamashita H,
Yoshioka D, Hirata I, et al. Effect of MDR1 gene
promoter methylation in patients with ulcerative
colitis. Int J Mol Med. 2009;23(4):521-7.
[23] Tahara T, Shibata T, Okubo M, Horiguchi N,
Emura S, Kawamura T, et al. DNA methylation of
genes in colorectum is a risk factor for the devel-
opment of ulcerative colitis-associated colorectal
cancer. Scand J Gastroenterol. 2014;49(9):1075-
82.
[24] Thiebaut F, Tsuruo T, Hamada H, Gottesman
MM, Pastan I, Willingham MC. Cellular localiza-
tion of the multidrug-resistance gene product P-
glycoprotein in normal human tissues. Proc Natl
Acad Sci U S A. 1987;84(21):7735-8.
[25] Ungaro R, Mehandru S, Allen PB, Peyrin-
Biroulet L, Colombel JF. Ulcerative colitis.
Lancet. 2017;389(10080):1756-70.
[26] Ventham NT, Kennedy NA, Nimmo ER, Satsangi
J. Beyond gene discovery in in ammatory bowel
disease: the emerging role of epigenetics. Gas-
troenterology. 2013;145(2):293-308.
[27] Wells GA, Shea B, OConnell D, Peterson J, Welch
V, Losos M, et al. The Newcastle-Ottawa Scale
(NOS) for assessing the quality of nonrandomised
studies in meta-analyses. Ottawa (ON): Ottawa
Hospital Research Institute; 2014.
[28] Mller K, Camelin M, Vatn S, Scharl M, Rehrauer
H, Frey-Wagner I, et al. ABCB1 promoter methy-
lation is a biomarker for relapse in ulcerative
colitis patients in remission. J Crohns Colitis.
2020;14(11):1539-1549.
[29] OConnell J, Boland K, Kelleher D, OShea NR,
Hevey D, McNamara D, et al. ABCB1 pro-
moter methylation as a biomarker of non-response
to in iximab in ulcerative colitis. Epigenomics.
2021;13(15):1199-1210.
[30] Wang L, Li P, Tang W, Li L,Wang J. Dietary ber
and butyrate prevent intestinal barrier dysfunc-
tion and ABCB1 hypermethylation in a mouse
model of colitis. J Nutr Biochem. 2022;105:109015.
[31] Cohen E, Silverberg MS, Jones JL, St-Pierre D,
Aumais G, Bitton A, et al. Rectal ABCB1 Methy-
lation Predicts Relapse in Inactive Ulcerative Col-
itis: A Prospective Multicenter Cohort Study. Am
J Gastroenterol. 2024;119(1):97-106.
[1] Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE,
Gottesman MM. P-glycoprotein: from genomics
to mechanism. Oncogene. 2003;22(47):7468-85.
[2] Blokzijl H, Vander Borght S, Bok LI, De Smet
M, Weemaes R, Roskams T, et al. Decreased
P-glycoprotein (P-gp/MDR1) expression in in-
amed human intestinal epithelium is indepen-
dent of PXR protein levels. In amm Bowel Dis.
2007;13(6):710-20.
[3] Camilleri M. Leaky gut: mechanisms, measure-
ment and clinical implications in humans. Gut.
2019;68(8):1516-26.
[4] Chen F, Wang Y, Wang H, Wang F. Resvera-
trol ameliorates DSS-induced ulcerative colitis by
regulating the gut microbiota and reversing the
ABCB1 promoter hypermethylation. Food Funct.
2019;10(12):7965-76.
[5] Courthod G, Adar T, Eliakim R, Shomron N. Pro-
moter hypermethylation of the ABCB1 gene is a
novel prognostic biomarker in ulcerative colitis. J
Crohns Colitis. 2015;9(6):467-73.
[6] Cui G, Jing J, He H, Tang S, Gong Z. DNA methy-
lation of the multidrug resistance gene 1 in ulcer-
ative colitis and its relationship with the risk of
colorectal cancer. Mol Med Rep. 2016;14(5):4557-
63.
[7] Danese S, Fiocchi C. Ulcerative colitis. N Engl J
Med. 2019;381(16):1551-62.
[8] Gazouli M, Pachoula I, Panayotou I, Goutas N,
Mantzaris G, Anagnou NP, et al. Hypermethyla-
tion of the PGP gene promoter in patients with in-
ammatory bowel disease. World J Gastroenterol.
2010;16(27):3371-7.
[9] Gottesman MM, Pastan I, Ambudkar SV. P-
glycoprotein and multidrug resistance. Curr Opin
Genet Dev. 1996;6(5):610-7.
[10] Hsler R, Feng Z, Bckdahl L, Spehlmann ME,
Franke A, Teschendorff A, et al. A functional
methylome map of ulcerative colitis. Genome Res.
2012;22(11):2130-7.
[11] Hooijmans CR, Rovers MM, de Vries RB,
Leenaars M, Ritskes-Hoitinga M, Langendam
MW. SYRCLEs risk of bias tool for animal stud-
ies. BMC Med Res Methodol. 2014;14:43.
[12] Ikeda Y, Nakatani K, Nagahama K, Kurokawa
S, Ota T, Kajimoto K, et al. Mesalamine in-
hibits DNA methyltransferase and restores P-
glycoprotein expression in Caco-2 cells. Biochem
Biophys Res Commun. 2018;499(3):477-82.
[13] Jones PA. Functions of DNA methylation: is-
lands, start sites, gene bodies and beyond. Nat
Rev Genet. 2012;13(7):484-92.
[14] Kaplan GG, Ng SC. Understanding and prevent-
ing the global increase of in ammatory bowel dis-
ease. Gastroenterology. 2017;152(2):313-21.e2.
[15] Kellermayer R. Epigenetics and the developmental
origins of in ammatory bowel diseases. Can J Gas-
troenterol. 2012;26(12):909-15.16. Langmann T,
Moehle C, Mauerer R, Scharl M, Lieb-Rebmann
V, Gregor M, et al. Gene expression of the tran-
scriptional coactivator PGC-1alpha is decreased in
experimental and human in ammatory bowel dis-
ease. Gut. 2004;53(11):1644-51.
[16] Li Y, Deuring J, Peppelenbosch MP, Kuipers EJ,
van der Woude CJ. IL-6-induced DNMT1 ac-
tivity mediates SOCS3 promoter hypermethyla-
tion in ulcerative colitis-related colorectal cancer.
Carcinogenesis. 2012;33(10):1889-96.18. Liu Z, Liu
Y, Li Y, Liu C, Wang J, Xiao H, et al. Cur-
cumin reverses the epithelial-mesenchymal tran-
sition and restores P-glycoprotein expression in a
model of colitis-associated cancer. J Ethnophar-
macol. 2020;253:112653.
[17] Matsumura K, Tahara T, Fukuyama M, Otsuka
T, Funasaka K, Ozaki K, et al. Clinical signif-
icance of ABCB1 promoter methylation in pa-
tients with ulcerative colitis. J Clin Biochem Nutr.
2019;65(3):234-9.
ABCB1 Promoter Methylation: A Potential Biomarker ...: 31{37 36
[18] Ng SC, Shi HY, Hamidi N, Underwood FE, Tang
W, Benchimol EI, et al. Worldwide incidence and
prevalence of in ammatory bowel disease in the
21st century: a systematic review of population-
based studies. Lancet. 2018;390(10114):2769-78.
[19] Page MJ, McKenzie JE, Bossuyt PM, Boutron I,
Hoffmann TC, Mulrow CD, et al. The PRISMA
2020 statement: an updated guideline for report-
ing systematic reviews. BMJ. 2021;372:n71.
[20] Panwala CM, Jones JC, Viney JL. A novel
model of in ammatory bowel disease: mice de-
cient for the multiple drug resistance gene,
mdr1a, spontaneously develop colitis. J Immunol.
1998;161(10):5733-44.
[21] Sadeghi H, Zare-Bidaki M, Zivari-Rahman M,
Kazemi-Nia AR, Fakhari H. High frequency of
ABCB1 promoter methylation in ulcerative col-
itis patients. Gastroenterol Hepatol Bed Bench.
2020;13(4):341-7.24. Schmidt C, Gaser C, Kret-
zschmar V, Schrmann S, Brckner S, Gerlach U,
et al. DNA methylation of the ABCB1 promoter
is a predictive biomarker for response to gluco-
corticoids in ulcerative colitis. Clin Epigenetics.
2018;10:19.
[22] Tahara T, Shibata T, Nakamura M, Yamashita H,
Yoshioka D, Hirata I, et al. Effect of MDR1 gene
promoter methylation in patients with ulcerative
colitis. Int J Mol Med. 2009;23(4):521-7.
[23] Tahara T, Shibata T, Okubo M, Horiguchi N,
Emura S, Kawamura T, et al. DNA methylation of
genes in colorectum is a risk factor for the devel-
opment of ulcerative colitis-associated colorectal
cancer. Scand J Gastroenterol. 2014;49(9):1075-
82.
[24] Thiebaut F, Tsuruo T, Hamada H, Gottesman
MM, Pastan I, Willingham MC. Cellular localiza-
tion of the multidrug-resistance gene product P-
glycoprotein in normal human tissues. Proc Natl
Acad Sci U S A. 1987;84(21):7735-8.
[25] Ungaro R, Mehandru S, Allen PB, Peyrin-
Biroulet L, Colombel JF. Ulcerative colitis.
Lancet. 2017;389(10080):1756-70.
[26] Ventham NT, Kennedy NA, Nimmo ER, Satsangi
J. Beyond gene discovery in in ammatory bowel
disease: the emerging role of epigenetics. Gas-
troenterology. 2013;145(2):293-308.
[27] Wells GA, Shea B, OConnell D, Peterson J, Welch
V, Losos M, et al. The Newcastle-Ottawa Scale
(NOS) for assessing the quality of nonrandomised
studies in meta-analyses. Ottawa (ON): Ottawa
Hospital Research Institute; 2014.
[28] Mller K, Camelin M, Vatn S, Scharl M, Rehrauer
H, Frey-Wagner I, et al. ABCB1 promoter methy-
lation is a biomarker for relapse in ulcerative
colitis patients in remission. J Crohns Colitis.
2020;14(11):1539-1549.
[29] OConnell J, Boland K, Kelleher D, OShea NR,
Hevey D, McNamara D, et al. ABCB1 pro-
moter methylation as a biomarker of non-response
to in iximab in ulcerative colitis. Epigenomics.
2021;13(15):1199-1210.
[30] Wang L, Li P, Tang W, Li L,Wang J. Dietary ber
and butyrate prevent intestinal barrier dysfunc-
tion and ABCB1 hypermethylation in a mouse
model of colitis. J Nutr Biochem. 2022;105:109015.
[31] Cohen E, Silverberg MS, Jones JL, St-Pierre D,
Aumais G, Bitton A, et al. Rectal ABCB1 Methy-
lation Predicts Relapse in Inactive Ulcerative Col-
itis: A Prospective Multicenter Cohort Study. Am
J Gastroenterol. 2024;119(1):97-106.
)