期刊
CANCER BIOLOGY & THERAPY
卷 22, 期 1, 页码 55-65出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15384047.2020.1856756
关键词
Epigenetic therapy; decitabine; demethylation; FBW7; Mcl-1; ubiquitination; Bcl2 inhibitor; lung cancer
类别
资金
- NIH/NCI [R01CA200905, R01CA193828, R01CA136534, P50CA217691]
- Winship Research Informatics, Pathology, and Integrated Cellular Imaging shared resource
- Winship Cancer Institute of Emory University [P30CAJ38292]
- Winship Fashion a Cure Research Scholar Award
- Winship Cancer Institute of Emory University
- Winship Endowment Fund
- National Cancer Institute [R01CA200905, R01CA193828, R01CA136534, P50CA217691]
Methylation of tumor suppressor genes in human lung cancer can be reversed by DAC, leading to activation of FBW7 and degradation of Mcl-1 protein, thereby inhibiting tumor growth. DAC treatment converts the FBW7 gene from a methylated to an unmethylated form, resulting in increased FBW7 expression and decreased Mcl-1 levels, ultimately suppressing lung cancer growth. Combination therapy with DAC and Venetoclax shows strong synergistic effects against lung cancer without causing normal tissue toxicity.
Methylation induces epigenetic silencing of tumor suppressor genes in human lung cancer. Inhibition of DNA methyltransferases by decitabine (DAC) can demethylate and activate epigenetically silenced tumor suppressor genes. Epigenetic therapy using DAC should be an attractive strategy for lung cancer therapy. FBW7 is a tumor suppressor that functions as an Mcl-1 E3 ligase to degrade Mcl-1 by ubiquitination. Here we discovered that treatment of various human lung cancer cells with DAC resulted in activation of FBW7 expression, decreased levels of Mcl-1 protein, and growth inhibition. DAC-activated FBW7 expression promoted Mcl-1 ubiquitination and degradation leading to a significant reduction in the half-life of Mcl-1 protein. Mechanistically, treatment of lung cancer cells or lung cancer xenografts with DAC induced the conversion of the FBW7 gene from a methylated form to an unmethylated form, which was associated with the increased expression of FBW7 and decreased expression of Mcl-1 in vitro and in vivo. DAC suppressed lung cancer growth in a dose-dependent manner in vivo. Combined treatment with DAC and a Bcl2 inhibitor, venetoclax, exhibited strong synergistic potency against lung cancer without normal tissue toxicity. These findings uncover a novel mechanism by which DAC suppresses tumor growth by targeting the FBW7/Mcl-1 signaling pathway. Combination of DAC with Bcl2 inhibitor venetoclax provides more effective epigenetic therapy for lung cancer.
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