CircIMMP2L promotes esophageal squamous cell carcinoma malignant progression via CtBP1 nuclear retention dependent epigenetic modification

Abstract

Background Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers. The two major lethal causes of ESCC are diagnosis at an advanced stage and lymph node metastasis (LNM). Circular RNAs (circRNAs) play critical regulatory roles in cancer progression, though, largely through unclear mechanisms. However, the character of circRNAs in the malignant progression of ESCC remains unclear. Methods The circRNA microarray was used to explore the circRNAs that were differentially expressed between ESCC and paired adjacent normal tissues. The function of circIMMP2L was validated by gain or loss of function assays. Pull‐down, RNA immunoprecipitation assays were used to demonstrate the biological mechanism of circIMMP2L. Tissue microarray (TMA), specimen, and paired plasma were investigated to evaluate the clinical significance of circIMMP2L. Results CircIMMP2L, commonly upregulated in tumor and plasma from advanced‐stage ESCC patients and LNM patients, predicts poorer patient survival. CircIMMP2L was also found to be a significant indicator for LNM, even in the T1 stage of ESCC. CircIMMP2L depletion suppressed the malignant progression of ESCC both in vitro and in vivo. Mechanistically, cytoplasmic circIMMP2L interacted with CtBP1 and facilitated the nuclear retention of CtBP1 in a CtBP2‐independent manner. Moreover, circIMMP2L promoted the interaction of CtBP1 with HDAC1 in the nucleus, which is essential for epigenetic remodeling and transcriptional suppression of E‐cadherin and p21. Conclusions These findings demonstrated that circIMMP2L promotes the malignant progression of ESCC mediated by CtBP1 nuclear retention and is a robust biomarker for the diagnosis, prognosis, and LNM in ESCC. Further, the findings extend our knowledge about the mechanism of circRNA regulation of gene transcription through epigenetics.

Circular RNA hsa_circ_0003823 promotes the Tumor Progression, Metastasis and Apatinib Resistance of Esophageal Squamous Cell Carcinoma by miR-607/CRISP3 Axis

“…Liu Z focused on the role of circDOPEY2 and concluded that circDOPEY2 inhibited CPEB4-mediated Mcl-1 translation process and enhanced chemosensitivity of ESCC 48 . Liang Y reported that CircIMMP2L promoted ESCC progression via CtBP1 nuclear retention dependent epigenetic modification 49 . We discovered a novel circRNA named hsa_circ_0003823 by identifying the circRNA and mRNA expression profiles of 3 pairs of ESCC tumor and paracancerous tissues, which was also the most up-regulated circRNA in tumor tissues.…”

circRNA: A New Biomarker and Therapeutic Target for Esophageal Cancer

“…Several studies have shown that circRNAs are involved in epigenetic regulation, including histone and chromatin modifications. circIMMP2L mediates the malignancy of esophageal squamous cell carcinoma (ESCC) by promoting the nuclear retention of CtBP1 [ 44 ]. In the nucleus, circIMMP2L mediates the interaction between CtBP1 and HDAC1 and induces the deacetylation of histone H3 in the promoter regions of E-cadherin and p21 .…”

“…circIMMP2L (hsa_circ_0081964) is derived from exons 2–4 of the Inner Mitochondrial Membrane Peptidase Subunit 2 ( IMMP2L ) gene. circIMMP2L has significantly higher expression in ESCC tissues from patients with an advanced TNM stage and lymph node metastasis [ 44 ]. The expression of plasma circIMMP2L in patients with advanced-stage ESCC or lymph node metastasis was significantly upregulated compared to that in healthy individuals.…”

“…The expression of plasma circIMMP2L in patients with advanced-stage ESCC or lymph node metastasis was significantly upregulated compared to that in healthy individuals. Quantification of circIMMP2L in plasma exhibited a relatively good diagnostic performance for the detection of lymph node metastasis, with an AUC of 0.865 [ 44 ].…”

Self-restricted circular RNA circSOX2 suppressed the malignant progression in SOX2-amplified LUSC

“…Numerous studies have reported the role of circRNA in almost every activity of life mediated by protein sponging. CircPOK increased the IL6 transcript by combining with ILF2/3 to occupy the promoter of IL6 [ 16 ]; The circIMMP2L regulated epigenetic remolding in esophageal squamous cell carcinoma by inducing CtBP1 nucleus retention [ 17 ]; The circACC1 up-regulated the glycolysis and β-oxidation by ensuring the stability of AMP-activated protein kinase (AMPK) protein [ 18 ]; The circVAMP3 negatively regulated hepatocellular carcinoma (HCC) mediated by cell cycle-associated protein 1 (CAPRIN1) and Stress Granule Assembly Factor 1 (G3BP1) interaction-dependent phase separation [ 19 ]. Some nuclear-localized circRNAs played roles in the splicing and transcription of its cognate endogenous transcript [ 20 , 21 ].…”