The RB Tumor Suppressor Positively Regulates Transcription of the Anti-angiogenic Protein NOL7

Abstract

The expression of the angiogenic phenotype is regulated by a balance of pro-angiogenic and anti-angiogenic factors released into the tumor microenvironment. Nuclear protein 7 (NOL7), a novel tumor suppressor, acts as a master regulator of angiogenesis by downregulating pro-angiogenic factors and upregulating anti-angiogenic factors. Using cervical cancer as a model of investigation, we have previously shown that loss of NOL7 mRNA and protein expression is observed as early as the premalignant phase. Analysis of the gene failed to identify tumor-specific promoter methylation or coding region mutations, suggesting that NOL7 loss may be mediated by aberrant expression of its upstream regulators. In this study, we show that the RB tumor suppressor gene (RB) positively regulates NOL7 at the transcriptional level by recruiting transcription factors and transcription machinery proteins to its promoter region. Conversely, the loss of RB represses NOL7 transcription by inhibiting assembly of these proteins. This loss of NOL7 expression is also observed in RB-deficient human malignancies. Together, this work further characterizes the transcriptional activator function of RB and defines a potential role for RB in regulating angiogenesis through activation of NOL7. Current anti-angiogenic therapies lack long-term efficacy, as they are unable to target the diverse angiogenic signals generated by tumors. Our data provide evidence to support the hypothesis that reactivation of pRB can potentially modulate the expression of the angiogenic phenotype through regulation of NOL7. Therefore, this knowledge may be employed to design more comprehensive and effective therapies.