Meng P, Ghosh R
Department of Urology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
1] Department of Urology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA [2] Department of Pharmacology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA [3] Department of Molecular Medicine, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA [4] Cancer Therapy and Research Center, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Cell Death Dis. 2014 Aug 7;5(8):e1360. doi: 10.1038/cddis.2014.326.
Classically, as a transcription factor family, the E2Fs are known to regulate the expression of various genes whose products are involved in a multitude of biological functions, many of which are deregulated in diseases including cancers. E2F is deregulated and hyperactive in most human cancers with context dependent, dichotomous and contradictory roles in almost all cancers. Cancer cells have an insatiable demand for transcription to ensure that gene products are available to sustain various biological processes that support their rapid growth and survival. In this context, cutting-off hyperactivity of transcription factors that support transcription dependence could be a valuable therapeutic strategy. However, one of the greatest challenges of targeting a transcription factor is the global effects on non-cancerous cells given that they control cellular functions in general. Recently, there is growing realization regarding the possibility to target the oncogenic activation of transcription factors to modulate transcription addiction without affecting the normal activity required for cell functions. In this review, we used E2F1 as a prototype transcription factor to address transcription factor activity in cancer cell functions. We focused on melanoma considering that E2F1 executes critical functions in response to UV, an etiological factor of cutaneous melanoma and lies immediately downstream of the CDKN2A/pRb axis, which is frequently deregulated in melanoma. Further, activation of E2F1 in melanomas can also occur independent of loss of CDKN2A. Given its activated status and the ability to transcriptionally control a plethora of genes involved in regulating melanoma development and progression, we review the current literature on its differential role in controlling signaling pathways involved in melanoma as well as therapeutic resistance, and discuss the practical value of weaning melanoma cells from E2F1-mediated transcription dependence for melanoma management.
传统上，作为一个转录因子家族，E2Fs已知可调节多种基因的表达，这些基因的产物参与众多生物学功能，其中许多在包括癌症在内的疾病中失调。E2F在大多数人类癌症中失调且过度活跃，在几乎所有癌症中具有依赖于背景的、二分法的和相互矛盾的作用。癌细胞对转录有着无尽的需求，以确保有基因产物可维持支持其快速生长和存活的各种生物学过程。在这种情况下，切断支持转录依赖性的转录因子的过度活性可能是一种有价值的治疗策略。然而，靶向转录因子的最大挑战之一是对非癌细胞的全局影响，因为它们总体上控制着细胞功能。最近，人们越来越意识到有可能靶向转录因子的致癌激活来调节转录成瘾，而不影响细胞功能所需的正常活性。在本综述中，我们以E2F1作为转录因子原型来探讨其在癌细胞功能中的活性。我们聚焦于黑色素瘤，因为E2F1在应对紫外线（皮肤黑色素瘤的一个病因）时发挥关键功能，且位于CDKN2A/pRb轴的下游，而该轴在黑色素瘤中经常失调。此外，黑色素瘤中E2F1的激活也可能独立于CDKN2A的缺失而发生。鉴于其激活状态以及转录控制大量参与调节黑色素瘤发生和进展的基因的能力，我们综述了当前关于其在控制黑色素瘤相关信号通路以及治疗抗性中的不同作用的文献，并讨论了使黑色素瘤细胞摆脱E2F1介导的转录依赖性对黑色素瘤治疗的实际价值。
