Targeting Hexokinase 2 Increases the Sensitivity of Oxaliplatin by Twist1 in Colorectal Cancer

Overview

Journal J Cell Mol Med

Specialties Cell Biology
Molecular Biology

Date 2021 Aug 11

PMID 34378321

Citations 12

Authors

Bo Zhang

Sze-Hoi Chan

Xue-Qi Liu

Yuan-Yuan Shi

Zhao-Xia Dong

Xin-Rong Shao

Li-Yuan Zheng

Zhi-Ying Mai

Tian-Liang Fang

Li-Zhi Deng

Di-Sheng Zhou

Shu-Na Chen

Miao Li

Xing-Ding Zhang

Affiliations

Soon will be listed here.

Abstract

Colorectal cancer (CRC) is the third most malignant tumour worldwide, with high mortality and recurrence. Chemoresistance is one of the main factors leading to metastasis and poor prognosis in advanced CRC patients. By analysing the Gene Expression Omnibus data set, we found higher hexokinase 2 (HK2) expression levels in patients with metastatic CRC than in those with primary CRC. Moreover, we observed higher enrichment in oxaliplatin resistance-related gene sets in metastatic CRC than in primary CRC. However, the underlying relationship has not yet been elucidated. In our study, HK2 expression was significantly elevated in CRC patients. Gene set enrichment analysis (GSEA) revealed multi-drug resistance and epithelial-mesenchymal transition (EMT) pathways related to high HK2 expression. Our results showed that knockdown of HK2 significantly inhibited vimentin and Twist1 expression and promoted TJP1 and E-cadherin expression in CRC cells. Additionally, transcriptional and enzymatic inhibition of HK2 by 3-bromopyruvate (3-bp) impaired oxaliplatin resistance in vitro and in vivo. Mechanistically, HK2 interacts with and stabilized Twist1 by preventing its ubiquitin-mediated degradation, which is related to oxaliplatin resistance, in CRC cells. Overexpression of Twist1 reduced the apoptosis rate by HK2 knockdown in CRC cells. Collectively, we discovered that HK2 is a crucial regulator that mediates oxaliplatin resistance through Twist1. These findings identify HK2 and Twist1 as promising drug targets for CRC chemoresistance.

Citing Articles

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TWIST1 regulates HK2 ubiquitination degradation to promote pancreatic cancer invasion and metastasis.

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Oxaliplatin and 5-fluorouracil promote epithelial-mesenchymal transition via activation of KRAS/ERK/NF-κB pathway in KRAS-mutated colon cancer cells.

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