An Update on the Potential Roles of E2F Family Members in Colorectal Cancer

Figures & data

Figure 1 Graphical illustration showing that the regulatory mechanisms for E2Fs in CRC. For instance, E2Fs function in CRC is modulated via multiple levels including the transcriptional level (NFYB, KRT23, and ChoKa inhibitors-mediated transcription of the E2F gene), post-transcriptional regulation (E2F mRNA targeted by different miRNAs and ceRNAs), post-translational modifications (deacetylation and acetylation of E2F protein), protein–protein interaction level (phosphorylation and dephosphorylation of RB protein), and transcriptional activity level (XIAPΔRING, TRIP-Br2, cIAP1, NLK, and NPTX1 regulate the transcriptional activity of E2Fs protein). Solid arrows represent promoted effects, while dashed arrows represent inhibitory effects. Different colored lines showed different signaling pathways or targets.

Abbreviations: DDR, DNA damage response; CSC, cancer stem cell; EMT, epithelial-mesenchymal transition.

Table 1 E2Fs-Target Agents Summary in CRC

Agents	Properties	Target	Anticancer Effects	Reference
Nanoliposomes	SUVs loaded with siE2F1	E2F1	Inhibiting the growth of colon carcinoma cells.	[^Citation116]
Resveratrol	Polyphenolic compound (isolated from grapes, peanuts or berries)	E2F1 E2F3	1. Enhancing the growth inhibition of colon carcinoma cells and cell apoptosis by targeting miR-34a/E2F3/Sirt1 and PI3K/Akt signaling pathway. 2. Enhancing the TTP inhibitory activity in CRC cells by negatively regulating cIAP2, E2F1, LATS2 and Lin28 expression.	[^Citation117,Citation118]
Tetrandrine	Bis-benzylisoquinoline alkaloid (isolated from the root of Stephania tetrandra)	E2F1	Inducing early G1 arrest by downregulating E2F1 and upregulating p53/p21^Cip1.	[^Citation58]
Ethanol extract of Innotus obliquus	Bioactive compounds	E2F1	Inducing G1 cell arrest and inhibiting cell proliferation by decreasing RB phosphorylation and E2F1 expression.	[^Citation121]
Non-digestible fraction of beans	Common beans extraction	E2F1	Exhibiting apoptosis induction, cell-cycle arrest, inhibition of cell proliferation and inflammation and induction of DNA repair.	[^Citation122]
3,3ʹ-Diindolylmethane	Indole derivative	E2F1	Inducing G1 and G2/M phase cell cycle arrest mediated by reduced CDK activity and E2F1.	[^Citation123]
Ixocarpalactone A	A withanolides extract from Mexican tomatillo	E2F1	Exerting potent antiproliferative and apoptotic activity in SW480 cells by modulating E2F1 and Bcl-2 family.	[^Citation124]
HQGGT	Traditional Chinese Herbal Medicine	E2F1	Suppressing CRC cell growth and promoting apoptosis in vivo and vitro xenografts; enhanced CRC cell sensitivity to 5-FU via suppressing the E2F1/TS signaling pathway.	[^Citation125]
Curcumin	A polyphenolic phytochemical isolated from the plant Curcuma longa	E2F4	ROS produced by curcumin is responsible for the cell growth inhibition and the downregulation of E2F4 expression.	[^Citation126]
EF31 and UBS109	Curcumin analogues	E2F1	Inducing cell cycle arrest through downregulation of signaling proteins	[^Citation127]
Cobimetinib	MEK inhibitor	E2F1	Inhibiting cell proliferation and inducing G1 phase arrest and apoptosis in HCT116 cells; enhancing the efficacy of 5-FU.	[^Citation128]
Fucoidan	Natural sulfated polysaccharide present in various brown algae	E2Fs	Exhibiting anticancer effects through the induction of cell cycle arrest and apoptosis regardless of the p53 status.	[^Citation129]
Triptolide/Minnelide	A natural compound isolated from the Chinese herb Tripterygium wilfordii/Its soluble analog	E2F1	Inducing apoptosis at low concentrations and E2F-dependent G1 phase arrest at higher concentrations.	[^Citation130,Citation131]
PHY906	Traditional Chinese Herbal Medicine	E2F1	Protecting the epithelial barrier against tumor cell invasion by modulating IFN-γ level and mediating cancer cell death.	[^Citation132]
Methylselenol	A selenium metabolite	E2F1	Regulating the expression of key genes related to cell cycle and apoptosis and inhibiting colon cancer cell proliferation and tumor growth.	[^Citation133]
Irinotecan	Topoisomerase I inhibitor	E2F1	Overcoming the resistance to 5-FU in combination with 5-FU pro-drugs on 5-FU-resistant colon tumors.	[^Citation134]

Abbreviations: SiE2F1, siRNA against the transcription factor E2F1; SUVs, small unilamellar vesicles; TTP, tristetraprolin; cIAP2, baculoviral IAP repeat containing 3; Lin 28, lin-28 homolog A; LATS2, large tumor suppressor kinase 2; HQGGT, Huang Qin Ge Gen Tang; TS, thymidylate synthase; ROS, reactive oxygen species; MEK, mitogen-activated protein kinase.

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