Complex Genetics Section, Division of Biomedical Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands.
J Clin Invest. 2010 Jun;120(6):2119-30. doi: 10.1172/JCI40583. Epub 2010 May 10.
The gene encoding COMM domain-containing 1 (COMMD1) is a prototypical member of the COMMD gene family that has been shown to inhibit both NF-kappaB- and HIF-mediated gene expression. NF-kappaB and HIF are transcription factors that have been shown to play a role in promoting tumor growth, survival, and invasion. In this study, we demonstrate that COMMD1 expression is frequently suppressed in human cancer and that decreased COMMD1 expression correlates with a more invasive tumor phenotype. We found that direct repression of COMMD1 in human cell lines led to increased tumor invasion in a chick xenograft model, while increased COMMD1 expression in mouse melanoma cells led to decreased lung metastasis in a mouse model. Decreased COMMD1 expression also correlated with increased expression of genes known to promote cancer cell invasiveness, including direct targets of HIF. Mechanistically, our studies show that COMMD1 inhibits HIF-mediated gene expression by binding directly to the amino terminus of HIF-1alpha, preventing its dimerization with HIF-1beta and subsequent DNA binding and transcriptional activation. Altogether, our findings demonstrate a role for COMMD1 in tumor invasion and provide a detailed mechanism of how this factor regulates the HIF pathway in cancer cells.
编码 COMM 结构域包含蛋白 1（COMMD1）的基因是 COMMD 基因家族的典型成员，已被证明可以抑制 NF-κB 和 HIF 介导的基因表达。NF-κB 和 HIF 是转录因子，已被证明在促进肿瘤生长、存活和侵袭中发挥作用。在这项研究中，我们证明 COMMD1 表达在人类癌症中经常受到抑制，并且 COMMD1 表达的降低与更具侵袭性的肿瘤表型相关。我们发现，在人类细胞系中直接抑制 COMMD1 会导致鸡异种移植物模型中的肿瘤侵袭增加，而在小鼠黑色素瘤细胞中增加 COMMD1 表达会导致小鼠模型中的肺转移减少。COMMD1 表达的降低也与已知促进癌细胞侵袭性的基因的表达增加相关，包括 HIF 的直接靶基因。从机制上讲，我们的研究表明 COMMD1 通过直接与 HIF-1alpha 的氨基末端结合来抑制 HIF 介导的基因表达，从而阻止其与 HIF-1beta 二聚化以及随后的 DNA 结合和转录激活。总之，我们的研究结果表明 COMMD1 在肿瘤侵袭中发挥作用，并提供了该因子如何在癌细胞中调节 HIF 途径的详细机制。
