Overview of E2F-1 and E2F-1-targeted Therapeutic Strategies

E2F-1, a member of the E2F family of transcription factors, is an important regulator of the cell cycle and the role of tumor suppressor proteins. E2F-1 is able to bind DNA and form heterodimers with dimerization partner (DP) proteins through the E2 recognition site. Dissociation of E2F-1 from the retinoblastoma (Rb) protein restores its transcriptional activity, thereby driving the cell cycle transition from G1 to S phase. E2F-1 not only activates its own transcription, but also activates the transcription of other genes involved in G1/S transition, such as DNA replication complexes (MCMs) and S-phase cyclins (E and A). In addition, E2F-1 can also induce apoptosis or suicide by increasing the expression of pro-apoptotic proteins Puma, Noxa and Bim, and inhibiting the expression of anti-apoptotic Bcl2 family protein Mcl1. Due to the important role of E2F-1 in cell proliferation and apoptosis, it has great significance and potential in disease treatment. For example, the E2F-1 promoter has been used in adenoviruses to drive the expression of the E1A adenovirus gene to induce selective killing in a variety of tumor cell lines. In addition, E2F-1 is also considered as a proliferation marker of breast tumors.

The Role of E2F-1 in Tumorigenesis and Development

E2F-1 has different expression patterns and functions in different types of tumors, and sometimes even has dual roles in the same tumor. For example, in small cell lung cancer, high expression of E2F-1 is associated with poor prognosis, but can also induce apoptosis. This may be because E2F-1 can activate some genes that promote cell cycle progression, such as cyclin E, cyclin A, and CDK2, so that cells enter S phase from G1 phase, increasing DNA replication stress and damage. At the same time, E2F-1 can also activate some genes that promote apoptosis, such as p73, p14ARF, Apaf-1, so that cells commit suicide under DNA damage or replication pressure. Therefore, E2F-1 has a dual role in small cell lung cancer, which can not only promote cell proliferation and malignant transformation, but also induce apoptosis and inhibit tumor growth. In breast cancer, high expression of E2F-1 is associated with tumor differentiation, invasion and metastasis, but can also inhibit angiogenesis. This may be because E2F-1 can promote the invasion and metastasis of breast cancer cells by regulating some genes related to cell migration and invasion, such as MMPs,has different expression patterns and functions in different types of tumors, and sometimes it even has dual roles in the same tumor. For example, in small cell lung cancer, high expression of E2F-1 is associated with a poor prognosis but can also induce apoptosis. This may be because E2F-1 can activate some genes that promote cell cycle progression, such as cyclin E, cyclin A, and CDK2, so that cells enter S phase from G1 phase, increasing DNA replication stress and damage. At the same time, E2F-1 can also activate some genes that promote apoptosis, such as p73, p14ARF, and Apaf-1, so that cells commit suicide under DNA damage or replication pressure. Therefore, E2F-1 has a dual role in small cell lung cancer, which can not only promote cell proliferation and malignant transformation but also induce apoptosis and inhibit tumor growth. In breast cancer, high expression of E2F-1 is associated with tumor differentiation, invasion, and metastasis but can also inhibit angiogenesis. This may be because E2F-1 can promote the invasion and metastasis of breast cancer cells by regulating some genes related to cell migration and invasion, such as MMPs, VEGF, and PDGFR. Meanwhile, E2F-1 can also induce angiogenesis by physically interacting with hypoxia-inducible factor 1 (HIF-1) to regulate the expression of vascular endothelial growth factor A (VEGFA). However, E2F-1 can also inhibit angiogenesis by activating thrombospondin 1 (TSP-1), an angiogenesis inhibitor. Therefore, E2F-1 also has a dual role in breast cancer, which can not only promote the invasion and metastasis of breast cancer cells but also inhibit angiogenesis and tumor growth.

E2F-1 can affect the proliferation and apoptosis of tumor cells by regulating cell cycle-related genes, tumor suppressor genes, or oncogenes. E2F-1 can activate some genes that promote G1/S transition, such as cyclin E, Cdc6, Cdc25A, PCNA, DHFR, and thymidine kinase. E2F-1 can also activate some apoptosis-inducing genes, such as p14ARF, p73, Apaf-1, caspase-3, caspase-7, Bim, Noxa, and PUMA. The mechanism of E2F-1-induced apoptosis may exist in two ways, p53-dependent and independent. The p53-dependent pathway of E2F-1-induced apoptosis is activated by the p14ARF gene, making its product bind to MDM2 protein, blocking the ubiquitination of p53 by MDM2, thereby stabilizing p53 protein, and activating downstream apoptosis effector molecules. The p53-independent pathway of E2F-1-induced apoptosis involves directly activating the p73 gene, making its product form a complex with E2F-1, and further activating apoptosis effector molecules such as Apaf-1, caspase-3, and caspase-7. Alternatively, E2F-1 directly activates BH3-only proteins such as Bim and Noxa to dissociate from the anti-apoptotic protein Bcl-2 or Bcl-xL, releasing Bax or Bak, resulting in increased mitochondrial outer membrane permeability and releasing Apoptotic effector molecules such as cytochrome C.

E2F-1 can also affect tumor invasion and metastasis by regulating angiogenesis-related genes, metastasis-related genes or immune-related genes. E2F-1 can promote angiogenesis and cell migration by activating VEGF-A, MMPs, CXCR4 and other genes. VEGF-A is an important angiogenic factor, which can bind to its receptor VEGFR, activate downstream MAPK, PI3K/AKT and other signaling pathways, and promote the proliferation, migration, permeability and survival of endothelial cells. E2F-1 can directly bind to the VEGF-A promoter region and enhance its transcriptional activity. E2F-1 can also inhibit angiogenesis and cell migration by inhibiting genes such as TSP-1 and PDGFR. E2F-1 can also affect the immune response by regulating CD80, IL-12 and other genes.

Regulation of E2F-1

The expression and function of E2F-1 are regulated by multiple factors, including signaling pathways, epigenetic modifications, and non-coding RNAs. The expression of E2F-1 is regulated by various signaling molecules such as growth factors, cell cycle proteins, and tumor suppressor proteins. For example, growth factors induce the expression of genes such as c-fos and c-jun by activating the Ras-MAPK pathway, thereby promoting the transcription of E2F-1. Cyclins such as cyclin D and cyclin E form a complex with CDK4 or CDK2, phosphorylate the tumor suppressor protein RB, and dissociate it from E2F-1, thereby activating the function of E2F-1. Tumor suppressor proteins such as p53 and pRB inhibit the function of E2F-1 by binding to E2F-1, inhibiting its transcriptional activity, or inducing its degradation. The transcriptional activity of E2F-1 is affected by epigenetic modifications such as methylation, acetylation, and phosphorylation in its promoter region and coding region. For example, high methylation levels in the E2F-1 promoter region correlated with low expression levels. The acetylation level of the E2F-1 coding region was positively correlated with its transcriptional activity. The phosphorylation level of the E2F-1 protein is positively correlated with its stability and function. In addition, the expression of E2F-1 is regulated by various non-coding RNAs, such as microRNAs and long non-coding RNAs. For example, the microRNA-17-92 cluster inhibits E2F-1 expression by targeting the 3'-untranslated region of E2F-1 mRNA, inhibiting its translation efficiency. Long non-coding RNA H19 inhibits the function of E2F-1 by binding to the E2F-1 protein and inhibiting its transcriptional activity.

Application and Prospect of E2F-1 in Disease Treatment

E2F-1 can be used as a therapeutic target or carrier to change its expression or activity in tumor cells through gene therapy, thereby inducing tumor cell apoptosis or inhibiting its proliferation. Gene therapy is a method that uses gene transfer technology to introduce foreign genes into target cells, thereby repairing or replacing defective genes or enhancing or inhibiting the expression of certain genes to achieve therapeutic purposes. As a transcription factor with dual functions, E2F-1 participates in cell cycle regulation in normal cells, induces apoptosis, and inhibits proliferation in tumor cells. Therefore, increasing the expression or activity of E2F-1 in tumor cells through gene therapy can effectively inhibit the development of tumors. For example, some studies have used recombinant adeno-associated virus (AAV) to transfect the E2F-1 gene into human colorectal cancer cells, and found that E2F-1 can induce apoptosis and interact with tumor suppressors such as p53 and p21. Gene synergy. In addition, studies have usedto transfect the E2F-1 gene into human colorectal cancer cells and found that E2F-1 can induce apoptosis and interact with tumor suppressors such as p53 and p21. Gene synergy. In addition, studies have used recombinant adenovirus to transfect the E2F-1 gene into human prostate cancer cells and found that E2F-1 can inhibit cell proliferation and cooperate with tumor suppressor genes such as PTEN.

E2F-1 can also be used as a drug target or sensitive factor to affect its interaction with Rb or other proteins or its transcriptional activity through drug intervention, thereby enhancing or weakening its effect on tumor cells. Drug intervention is a method that uses chemically synthesized or naturally extracted small molecule compounds to regulate the function of specific proteins or signaling pathways, so as to achieve therapeutic purposes. As an important transcription factor, E2F-1's activity is affected by various drugs. For example, studies have found that certain chemotherapeutic drugs such as paclitaxel, cisplatin, and doxorubicin can induce the expression of E2F-1 in tumor cells, and cooperate with tumor suppressor genes such as p53 to enhance the sensitivity of tumor cells to chemotherapeutic drugs sex. In addition, studies have found that certain targeted drugs such as mTOR inhibitors, EGFR inhibitors, HDAC inhibitors, can inhibit the expression or activity of E2F-1 in tumor cells, and cooperate with proto-oncogenes such as cyclin D to reduce the drug resistance of tumor cells to targeted drugs.

In addition, E2F-1 can be used as an epigenetic target or regulator to regulate its stability or function by changing its methylation, acetylation, ubiquitination, and other modification states, thereby affecting the fate of tumor cells. Epigenetics refers to the genetic phenomenon that changes the structure and function of DNA without changing the DNA sequence. Epigenetic modifications include DNA methylation, histone modification, non-coding RNA regulation, etc. E2F-1 is a transcription factor that is regulated at multiple levels, and its stability and function are affected by various epigenetic modifications. For example, studies have found that high methylation levels in the E2F-1 promoter region are associated with low expression levels and a poor prognosis in colorectal cancer patients. In addition, studies have found that acetylation of the E2F-1 protein can enhance its transcriptional activity and is associated with a good prognosis for breast cancer patients.

At present, some clinical trials for E2F-1 are underway or have been completed, mainly involving colorectal cancer, prostate cancer, melanoma, and other types of tumors, and the preliminary results show certain safety and efficacy. For example, in a phase I clinical trial of patients with advanced colorectal cancer, local injection of adeno-associated virus (AAV-E2F/p53), a dual carrier of E2F-1 and p53 genes, was used in combination with 5-FU chemotherapy. The results showed that AAV-E2F/p53 could effectively induce the expression of E2F-1 and p53 genes in colorectal cancer tissue without causing obvious adverse reactions. In addition, there is a phase I/II clinical trial in patients with advanced prostate cancer using local injection of an adeno-associated virus (AAV-E2F) containing a single vector of the E2F-1 gene combined with radiation therapy. The results showed that AAV-E2F can effectively induce the expression of the E2F-1 gene and p21, Bax, and other downstream genes in prostate cancer tissue without causing obvious adverse reactions.

Table 1. E2F-1-Related Drugs in Clinical or Marketed