Targeting hexokinase 2 increases the sensitivity of oxaliplatin by Twist1 in colorectal cancer

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.

Gastric cancer mesenchymal stem cells promote tumor glycolysis and chemoresistance by regulating B7H3 in gastric cancer cells

“…Knockdown of HK2 expression can enhance the sensitivity of ovarian cancer to cisplatin 15 . In colorectal cancer (CRC) cells, HK2 interacts with and stabilizes Twist1 by preventing its ubiquitin‐mediated degradation, which is associated with OXA resistance 16 . However, the relationship between the expression of glycolysis key enzyme HK2 and chemoresistance in GC needs to be further explored.…”

Detection and surveillance of circulating tumor cells in osteosarcoma for predicting therapy response and prognosis

“…Its role in tumorigenesis has been attributed to its glucose kinase activity 19 . HK2 expression is higher in patients with metastatic tumors than primary tumors 13,20,21 , and is associated with advanced tumor grades 21 . High expression of HK2 in tumor tissues is critical for the proliferation, migration, and chemoresistance of tumor cells [20][21][22] .…”

“…HK2 expression is higher in patients with metastatic tumors than primary tumors 13,20,21 , and is associated with advanced tumor grades 21 . High expression of HK2 in tumor tissues is critical for the proliferation, migration, and chemoresistance of tumor cells [20][21][22] . This functional marker enables the detection of CTCs with epithelial traits and EMT, particularly cytokeratin negative CTCs, on the basis of our recent studies [13][14][15][16] .…”

LncRNA HCG18 promotes Prostate Cancer progression by regulating miR-512-3p/HK-2 axis

“…Hexokinases are involved in the glycolytic process of tumor cells on the one hand and act on voltage-dependent ion channels to inhibit apoptosis on the other hand [21]. In addition, hexokinase has also been shown to be involved in tumor progression by affecting tumor vascular function, and Zhang et al showed that in colorectal cancer, HK-2 affects cellular sensitivity to drugs [17,22]. Therefore, HK-2 is now considered to be an important target for anti-cancer drugs [19].…”

“…Metabolic reprogramming is an important feature of tumor cell development [17]. In contrast to normal cells, tumor cells can obtain energy through anaerobic glycolysis even under oxygen-enriched conditions, a change known as the Warburg effect [18,19].…”