Tonicity-responsive enhancer-binding protein promotes stemness of liver cancer and cisplatin resistance.

Abstract

BACKGROUND:

High recurrence and chemoresistance drive the high mortality in hepatocellular carcinoma (HCC). Although cancer stem cells are considered to be the source of recurrent and chemoresistant tumors, they remain poorly defined in HCC. Tonicity-responsive enhancer binding protein (TonEBP) is elevated in almost all HCC tumors and associated with recurrence and death. We aimed to identify function of TonEBP in stemness and chemoresistance of liver cancer.

METHODS:

Tumors obtained from 280 HCC patients were analyzed by immunohistochemical analyses. Stemness and chemoresistance of liver CSCs (LCSCs) were investigated using cell culture. Tumor-initiating activity was measured by implanting LCSCs into BALB/c nude mice.

FINDINGS:

Expression of TonEBP is higher in LCSCs in HCC cell lines and correlated with markers of LCSCs whose expression is significantly associated with poor prognosis of HCC patients. TonEBP mediates ATM-mediated activation of NF-κB, which stimulates the promoter of a key stem cell transcription factor SOX2. As expected, TonEBP is required for the tumorigenesis and self-renewal of LSCSs. Cisplatin induces the recruitment of the ERCC1/XPF dimer to the chromatin in a TonEBP-dependent manner leading to DNA repair and cisplatin resistance. The cisplatin-induced inflammation in LSCSs is also dependent on the TonEBP-ERCC1/XPF complex, and leads to enhanced stemness via the ATM-NF-κB-SOX2 pathway. In HCC patients, tumor expression of ERCC1/XPF predicts recurrence and death in a TonEBP-dependent manner.

INTERPRETATION:

TonEBP promotes stemness and cisplatin resistance of HCC via ATM-NF-κB. TonEBP is a key regulator of LCSCs and a promising therapeutic target for HCC and its recurrence.

• Authors: Jun Ho Lee, Jae Hee Suh, Hyun Je Kang, Soo Youn Choi, Seok Won Jung, Whaseon Lee-Kwon, Soo-Ah Park, Hajin Kim, Byeong Jin Ye, Eun Jin Yoo, Gyu Won Jeong, Neung Hwa Park, Hyug Moo Kwon
• Journal: EBioMedicine (EBioMedicine) Vol. 58 Pg. 102926 (Aug 2020) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 32739873 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Biomarkers, Tumor
• DNA-Binding Proteins
• NFAT5 protein, human
• Transcription Factors
• xeroderma pigmentosum group F protein
• ERCC1 protein, human
• Endonucleases
• Cisplatin

Topics

• Animals
• Biomarkers, Tumor (metabolism)
• Carcinoma, Hepatocellular (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• DNA-Binding Proteins (metabolism)
• Drug Resistance, Neoplasm
• Endonucleases (metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Liver Neoplasms (genetics, metabolism, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Neoplastic Stem Cells (metabolism, pathology)
• Prognosis
• Transcription Factors (genetics)
• Up-Regulation
• Xenograft Model Antitumor Assays