| Induction of angiogenesis is a critical step that facilitates tumor growth and progression by supplying nutrients and oxygen. Current anti-angiogenic therapies lack long-term efficacy, as they are unable to target the diverse angiogenic signals generated by tumors. NOL7 is a novel anti-angiogenic protein, which may function as a master regulator of angiogenesis by upregulating anti-angiogenic and downregulating pro-angiogenic pathways. NOL7 expression is lost in the early premalignant phases of CC, however the mechanism behind this loss is not known. Analysis of the NOL7 gene failed to identify any tumor-specific promoter methylation or deleterious mutation in CC, thereby suggesting that loss of NOL7 may occur due to aberrant expression of its upstream regulators. Reactivation of pRB resulted in NOL7 mRNA upregulation, suggesting that pRB may positively regulate NOL7 transcription. This work demonstrates that pRB positively regulates NOL7 at the transcriptional level by recruiting transcription factors and proteins of the transcription machinery to its promoter region. RB loss represses NOL7 transcription by inhibiting assembly of these proteins. This NOL7 downregulation is also observed in human malignancies in which pRB is inactivated by various mechanisms. Further, conditional pRB loss mediated partial NOL7 repression was unable to shift cells to a more pro-angiogenic state. Moreover, exogenous NOL7 expression induced an anti-angiogenic state irrespective of pRB knockdown. These results indicate that pRB is upstream of the NOL7-mediated angioinhibitory pathway and may indirectly regulate angiogenesis by modulating NOL7 transcription. Together this work has characterized the transcriptional activation role of pRB and defined a potential role for pRB in inhibiting angiogenesis through activation of NOL7. Moreover, this knowledge can be utilized to design more effective anti-angiogenic therapies that have the potential to target multiple angiogenic pathways. |
