Transcription addiction: can we garner the Yin and Yang functions of E2F1 for cancer therapy?

Abstract

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.

Figure 1

Functional domains of E2F transcription factor family. On the basis of their ability to regulate downstream target genes, E2F family members are classified into two groups, activators (E2F1-3a) or repressors (E2F3b-8). As transcription factors, they all have the DBD, NLS, DD (dimerization domain), TAD, NES (nuclear exclusion signal; modified from Chen et al.)

Figure 2

E2F1 regulates several biological functions. E2F1 is known to upregulate many genes involved in cell cycle, DNA synthesis and replication, checkpoint control, DNA damage and repair, apoptosis, autophagy, self-renewal, development and differentiation, and so on.^{, , , , ,} E2F1 also represses antiapoptotic genes or survival pathways to induce apoptosis. Downregulation of E2F1 is related to senescence considering its role in promoting cell cycle progression

Figure 3

Involvement of E2F1 in cell cycle progression. After pRb is hyperphosphorylated, phosphorylation of E2F1 at Serine-332 and -337 by cyclin D/cdk4/6 complex at the G1/S transition point increases the stability of E2F1 and prevents pRb binding. Sequential acetylation of E2F1 at Lysine-117, -120, and -125 sites further stabilizes E2F1 and increases DNA-binding ability of E2F1/DP heterodimer. In late S phase, cdk2 recruited by cyclin A phosphorylates E2F1 at Serine-375, which causes the release of DP protein and reduces DNA-binding ability of E2F1 itself. This process facilitates the binding of p14^ARF to the carboxyl terminus of E2F1 and promotes subsequent binding of p45^skp2 to the amino terminus and leads to the degradation of E2F1 in S–G2 phase

Figure 4

E2F1 is involved in crosstalk with Ras–Raf–MEK–ERK and PI3K–AKT pathways. E2F1 promotes sustained AKT activation through Gab2, whereas AKT in turn inhibits E2F1-mediated apoptosis by activation of TopBP1. ERK1/2 is known to upregulate the expression of cyclin D1, which induces the activation of CDK4/6 and subsequently phosphorylates pRB to release E2F1. Meanwhile, E2F1 also regulates ERK activation via transactivation of RasGRP1 and RasGEF1B, which positively affects Ras activity. Thus E2F1 induces two positive feedback loops for survival