E2F1 in Melanoma Progression and Metastasis

Abstract

Metastases are responsible for cancer deaths, but the molecular alterations leading to tumor progression are unclear. Overexpression of the E2F1 transcription factor is common in high-grade tumors that are associated with poor patient survival. To investigate the association of enhanced E2F1 activity with aggressive phenotype, we performed a gene-specific silencing approach in a metastatic melanoma model. Knockdown of endogenous E2F1 via E2F1 small hairpin RNA (shRNA) expression increased E-cadherin expression of metastatic SK-Mel-147 melanoma cells and reduced their invasive potential but not their proliferative activity. Although growth rates of SK-Mel-147 and SK-Mel-103 xenograft tumors expressing E2F1 shRNA or control shRNA were similar, mice implanted with cells expressing E2F1 shRNA had a smaller area of metastases per lung than control mice (n = 3 mice per group; 5% vs 46%, difference = 41%, 95% confidence interval = 15% to 67%; P = .01; one-way analysis of variance). We identified epidermal growth factor receptor as a direct target of E2F1 and demonstrated that inhibition of receptor signaling abrogates E2F1-induced invasiveness, emphasizing the importance of the E2F1-epidermal growth factor receptor interaction as a driving force in melanoma progression that may serve as a paradigm for E2F1-induced metastasis in other human cancers.

Kinetic Modeling–Based Detection of Genetic Signatures That Provide Chemoresistance via the E2F1-p73/DNp73-miR-205 Network

“…From this perspective, aberrantly elevated E2F1 levels in high-grade tumors can be considered as a marker for unfavorable patient survival prognosis. In support of these findings, we have recently shown that dysregulated E2F1 causes malignant progression in therapy-resistant metastatic melanoma xenografts in which depletion of endogenously high E2F1 levels abrogates tumor invasion and pulmonary metastasis (10). According to our results, the aggressive behavior of E2F1 in melanoma cells is partially mediated through the induction of the EGF receptor (EGFR) pathway.…”

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

“…E2F1 plays an important role in regulating development, differentiation, proliferation, cellular signal transduction, and apoptosis (9)(10)(11)(12). Certain studies reported that E2F1 disrupts a range of pathways in numerous cancers and is closely correlated with clinical parameters (13)(14)(15). We had also previously identified that E2F1 is upregulated in ccRCC progression (16).…”

The Dark Side of E2F1: In Transit beyond Apoptosis

“…Our recent in vivo data provide the first functional evidence that E2F1 is crucial in transformed cells for local invasion and to form distant metastases (10). This study showed that knockdown of endogenous E2F1 in a metastatic melanoma model severely reduces the migratory and invasive potential of skin cancer cells, whereas cell proliferation is not affected.…”

“…Now the question arises of how E2F1 accomplishes tumor progression and whether this represents a more general paradigm beyond cell-cycle regulation. In malignant melanoma, E2F1-dependent progression was found to be mediated through the upregulation of EGFR and activation of the cytoplasmic Ras/mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) and PI3K/AKT signaling cascades, as well as B-Myb transactivation in vitro (10). It seems that the EGFR ligand HBEGF is also a transcriptional target of E2F1, providing the possibility for autocrine stimulation of EGFR signaling in aggressive skin cancer.…”