TY - JOUR
T1 - Bortezomib induces DNA hypomethylation and silenced gene transcription by interfering with Sp1/NF-κB-dependent DNA methyltransferase activity in acute myeloid leukemia
AU - Liu, Shujun
AU - Liu, Zhongfa
AU - Xie, Zhiliang
AU - Pang, Jiuxia
AU - Yu, Jianhua
AU - Lehmann, Esther
AU - Huynh, Lenguyen
AU - Vukosavljevic, Tamara
AU - Takeki, Mitsui
AU - Klisovic, Rebecca B.
AU - Baiocchi, Robert A.
AU - Blum, William
AU - Porcu, Pierluigi
AU - Garzon, Ramiro
AU - Byrd, John C.
AU - Perrotti, Danilo
AU - Caligiuri, Michael A.
AU - Chan, Kenneth K.
AU - Wu, Lai Chu
AU - Marcucci, Guido
PY - 2008/2/15
Y1 - 2008/2/15
N2 - Bortezomib reversibly inhibits 26S proteasomal degradation, interferes with NF-κB, and exhibits antitumor activity in human malignancies. Zinc finger protein Sp1 transactivates DNMT1 gene in mice and is functionally regulated through protein abundance, posttranslational modifications (ie, ubiquitination), or interaction with other transcription factors (ie, NF-κB). We hypothesize that inhibition of proteasomal degradation and Sp1/NF-κB- mediated transactivation may impair aberrant DNA methyltransferase activity. We show here that, in addition to inducing accumulation of polyubiquitinated proteins and abolishment of NF-κB activities, bortezomib decreases Sp1 protein levels, disrupts the physical interaction of Sp1/ NF-κB, and prevents binding of the Sp1/ NF-κB complex to the DNMT1 gene promoter. Abrogation of Sp1/NF-κB complex by bortezomib causes transcriptional repression of DNMT1 gene and downregulation of DNMT1 protein, which in turn induces global DNA hypomethylation in vitro and in vivo and re-expression of epigenetically silenced genes in human cancer cells. The involvement of Sp1/NF-κB in DNMT1 regulation is further demonstrated by the observation that Sp1 knockdown using mithramycin A or shRNA decreases DNMT1 protein levels, which instead are increased by Sp1 or NF-κB overexpression. Our results unveil the Sp1/NF-κB pathway as a modulator of DNA methyltransferase activity in human cancer and identify bortezomib as a novel epigenetic-targeting drug.
AB - Bortezomib reversibly inhibits 26S proteasomal degradation, interferes with NF-κB, and exhibits antitumor activity in human malignancies. Zinc finger protein Sp1 transactivates DNMT1 gene in mice and is functionally regulated through protein abundance, posttranslational modifications (ie, ubiquitination), or interaction with other transcription factors (ie, NF-κB). We hypothesize that inhibition of proteasomal degradation and Sp1/NF-κB- mediated transactivation may impair aberrant DNA methyltransferase activity. We show here that, in addition to inducing accumulation of polyubiquitinated proteins and abolishment of NF-κB activities, bortezomib decreases Sp1 protein levels, disrupts the physical interaction of Sp1/ NF-κB, and prevents binding of the Sp1/ NF-κB complex to the DNMT1 gene promoter. Abrogation of Sp1/NF-κB complex by bortezomib causes transcriptional repression of DNMT1 gene and downregulation of DNMT1 protein, which in turn induces global DNA hypomethylation in vitro and in vivo and re-expression of epigenetically silenced genes in human cancer cells. The involvement of Sp1/NF-κB in DNMT1 regulation is further demonstrated by the observation that Sp1 knockdown using mithramycin A or shRNA decreases DNMT1 protein levels, which instead are increased by Sp1 or NF-κB overexpression. Our results unveil the Sp1/NF-κB pathway as a modulator of DNA methyltransferase activity in human cancer and identify bortezomib as a novel epigenetic-targeting drug.
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U2 - 10.1182/blood-2007-08-110171
DO - 10.1182/blood-2007-08-110171
M3 - Article
C2 - 18083845
AN - SCOPUS:41349103438
SN - 0006-4971
VL - 111
SP - 2364
EP - 2373
JO - Blood
JF - Blood
IS - 4
ER -