TY - JOUR
T1 - Multifactorial regulation of E-cadherin expression
T2 - An integrative study
AU - Reinhold, William C.
AU - Reimers, Mark A.
AU - Lorenzi, Philip
AU - Ho, Jennifer
AU - Shankavaram, Uma T.
AU - Ziegler, Micah S.
AU - Bussey, Kimberly J.
AU - Nishizuka, Satoshi
AU - Ikediobi, Ogechi
AU - Pommier, Yves G.
AU - Weinstein, John N.
PY - 2010/1
Y1 - 2010/1
N2 - E-cadherin (E-cad) is an adhesion molecule associated with tumor invasion and metastasis. Its down-regulation is associated with poor prognosis for many epithelial tumor types. We have profiled E-cad in the NCI-60 cancer cell lines at the DNA, RNA, and protein levels using six different microarray platforms plus bisulfite sequencing. Here we consider the effects on E-cad expression of eight potential regulatory factors: E-cad promoter DNA methylation, the transcript levels of six transcriptional repressors (SNAI1, SNAI2, TCF3, TCF8, TWIST1, and ZFHX1B), and E-cad DNA copy number. Combined bioinformatic and pharmacological analyses indicate the following ranking of influence on E-cad expression: (1) E-cad promoter methylation appears predominant, is strongly correlated with E-cad expression, and shows a 20% to 30% threshold above which E-cad expression is silenced; (2) TCF8 expression levels correlate with (-0.62) and predict (P < 0.00001) E-cad expression; (3) SNAI2 and ZFHX1B expression levels correlate positively with each other (+0.83) and also correlate with (-0.32 and -0.30, respectively) and predict (P = 0.03 and 0.01, respectively) E-cad expression; (4) TWIST1 correlates with (-0.34) but does not predict E-cad expression; and (5) SNAI1 expression, TCF3 expression, and E-cad DNA copy number do not correlate with or predict E-cad expression. Predictions of E-cad regulation based on the above factors were tested and verified by demethylation studies using 5-aza-2′-deoxycytidine treatment; siRNA knock-down of TCF8, SNAI2, or ZFHX1B expression; and combined treatment with 5-aza-2′- deoxycytidine and TCF8 siRNA. Finally, levels of cellular E-cad expression are associated with levels of cell-cell adhesion and response to drug treatment.
AB - E-cadherin (E-cad) is an adhesion molecule associated with tumor invasion and metastasis. Its down-regulation is associated with poor prognosis for many epithelial tumor types. We have profiled E-cad in the NCI-60 cancer cell lines at the DNA, RNA, and protein levels using six different microarray platforms plus bisulfite sequencing. Here we consider the effects on E-cad expression of eight potential regulatory factors: E-cad promoter DNA methylation, the transcript levels of six transcriptional repressors (SNAI1, SNAI2, TCF3, TCF8, TWIST1, and ZFHX1B), and E-cad DNA copy number. Combined bioinformatic and pharmacological analyses indicate the following ranking of influence on E-cad expression: (1) E-cad promoter methylation appears predominant, is strongly correlated with E-cad expression, and shows a 20% to 30% threshold above which E-cad expression is silenced; (2) TCF8 expression levels correlate with (-0.62) and predict (P < 0.00001) E-cad expression; (3) SNAI2 and ZFHX1B expression levels correlate positively with each other (+0.83) and also correlate with (-0.32 and -0.30, respectively) and predict (P = 0.03 and 0.01, respectively) E-cad expression; (4) TWIST1 correlates with (-0.34) but does not predict E-cad expression; and (5) SNAI1 expression, TCF3 expression, and E-cad DNA copy number do not correlate with or predict E-cad expression. Predictions of E-cad regulation based on the above factors were tested and verified by demethylation studies using 5-aza-2′-deoxycytidine treatment; siRNA knock-down of TCF8, SNAI2, or ZFHX1B expression; and combined treatment with 5-aza-2′- deoxycytidine and TCF8 siRNA. Finally, levels of cellular E-cad expression are associated with levels of cell-cell adhesion and response to drug treatment.
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U2 - 10.1158/1535-7163.MCT-09-0321
DO - 10.1158/1535-7163.MCT-09-0321
M3 - Article
C2 - 20053763
AN - SCOPUS:73949100356
SN - 1535-7163
VL - 9
SP - 1
EP - 16
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 1
ER -