Competitive Binding Between Id1 and E2F1 to Cdc20 Regulates E2F1 Degradation and Thymidylate Synthase Expression to Promote Esophageal Cancer Chemoresistance

Abstract

Purpose: Chemoresistance is a major obstacle in cancer therapy. We found that fluorouracil (5-FU)-resistant esophageal squamous cell carcinoma cell lines, established through exposure to increasing concentrations of 5-FU, showed upregulation of Id1, IGF2, and E2F1. We hypothesized that these genes may play an important role in cancer chemoresistance.Experimental Design: In vitro and in vivo functional assays were performed to study the effects of Id1-E2F1-IGF2 signaling in chemoresistance. Quantitative real-time PCR, Western blotting, immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter assays were used to investigate the molecular mechanisms by which Id1 regulates E2F1 and by which E2F1 regulates IGF2. Clinical specimens, tumor tissue microarray, and Gene Expression Omnibus datasets were used to analyze the correlations between gene expressions and the relationships between expression profiles and patient survival outcomes.Results: Id1 conferred 5-FU chemoresistance through E2F1-dependent induction of thymidylate synthase expression in esophageal cancer cells and tumor xenografts. Mechanistically, Id1 protects E2F1 protein from degradation and increases its expression by binding competitively to Cdc20, whereas E2F1 mediates Id1-induced upregulation of IGF2 by binding directly to the IGF2 promoter and activating its transcription. The expression level of E2F1 was positively correlated with that of Id1 and IGF2 in human cancers. More importantly, concurrent high expression of Id1 and IGF2 was associated with unfavorable patient survival in multiple cancer types.Conclusions: Our findings define an intricate E2F1-dependent mechanism by which Id1 increases thymidylate synthase and IGF2 expressions to promote cancer chemoresistance. The Id1-E2F1-IGF2 regulatory axis has important implications for cancer prognosis and treatment. Clin Cancer Res; 22(5); 1243-55. Ó2015 AACR.

Significance of PI3K/AKT signaling pathway in metastasis of esophageal squamous cell carcinoma and its potential as a target for anti-metastasis therapy

“…The qRT-PCR was performed as described previously [51]. In brief, total RNA was isolated using Trizol reagent according to the manufacturer's protocol (Invitrogen).…”

Inhibitor of Differentiation/DNA Binding 1 (ID1) Inhibits Etoposide-induced Apoptosis in a c-Jun/c-Fos-dependent Manner

“…It is also known to be induced by Stat3 and then up-regulates MDM2 to promote p53 protein degradation (16). Moreover, ID1 increases thymidylate synthase dependent upon E2F1 to promote cancer chemoresistance (12). These findings indicate that ID1 expression associates with other molecular markers and may not be an independent prognostic factor.…”

“…A recent study revealed that competitive binding between ID1 and E2F1 to CDC20 regulates E2F1 degradation and thymidylate synthase expression to promote esophageal cancer chemoresistance (12). Moreover, another previous study showed that ID1 was also induced by nicotine, and ectopic expression of ID1 might enhance cell resistance to damage (13).…”

“…A recent study reported that competitive binding between ID1 and E2F1 to Cdc20 regulates E2F1 degradation and thymidylate synthase expression to promote esophageal cancer chemoresistance. The ID1-E2F1-IGF2 regulatory axis has important implications for cancer prognosis and treatment (12). These data indicate that ID1 is up-regulated by chemotherapeutic drugs and may be involved in chemoresistance.…”

“…The overexpression of ID1 is frequent (93%) in human primary ESCC (10). ID1 expression correlates directly with tumor invasion, metastasis, and poor prognosis in ESCC (6,11,12). Notably, ID1 was involved in chemotherapy and radiotherapy resistance in human cancers including pancreatic adenocarcinoma, breast cancer, lung cancer, colorectal cancer, and esophageal cancer and becomes a new potential therapeutic target (13)(14)(15)(16)(17).…”