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.

中文翻译：

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Twist1靶向己糖激酶2增加了奥沙利铂在结直肠癌中的敏感性

结直肠癌（CRC）是全球第三大恶性肿瘤，具有高死亡率和高复发率。化疗耐药是导致晚期CRC患者发生转移和预后不良的主要因素之一。通过分析 Gene Expression Omnibus 数据集，我们发现转移性 CRC 患者的己糖激酶 2 (HK2) 表达水平高于原发性 CRC 患者。此外，我们观察到转移性 CRC 中奥沙利铂耐药相关基因组的富集程度高于原发性 CRC。然而，潜在的关系尚未阐明。在我们的研究中，CRC 患者的 HK2 表达显着升高。基因集富集分析 (GSEA) 揭示了与 HK2 高表达相关的多药耐药性和上皮间质转化 (EMT) 途径。我们的研究结果表明，敲低 HK2 显着抑制波形蛋白和 Twist1 表达，并促进 CRC 细胞中 TJP1 和 E-钙粘蛋白的表达。此外，3-溴丙酮酸 (3-bp) 对 HK2 的转录和酶促抑制损害了奥沙利铂耐药性体外和体内。从机制上讲，HK2 通过阻止其泛素介导的降解（与奥沙利铂耐药性相关）在 CRC 细胞中与 Twist1 相互作用并使其稳定。Twist1 的过表达通过敲低 HK2 在 CRC 细胞中降低了细胞凋亡率。总的来说，我们发现 HK2 是通过 Twist1 介导奥沙利铂耐药的关键调节因子。这些发现将 HK2 和 Twist1 确定为 CRC 化学抗性的有希望的药物靶标。