HKDC1 upregulation promotes glycolysis and disease progression, and confers chemoresistance onto gastric cancer

Abstract

There is increasing evidence that hexokinase is involved in cell proliferation and migration. However, the function of the hexokinase domain containing protein‐1 (HKDC1) in gastric cancer (GC) remains unclear. Immunohistochemistry analysis and big data mining were used to evaluate the correlation between HKDC1 expression and clinical features in GC. In addition, the biological function and molecular mechanism of HKDC1 in GC were studied by in vitro and in vivo assays. Our study indicated that HKDC1 expression was upregulated in GC tissues compared with adjacent nontumor tissues. High expression of HKDC1 was associated with worse prognosis. Functional experiments demonstrated that HKDC1 upregulation promoted glycolysis, cell proliferation, and tumorigenesis. In addition, HKDC1 could enhance GC invasion and metastasis by inducing epithelial–mesenchymal transition (EMT). Abrogation of HKDC1 could effectively attenuate its oncogenic and metastatic function. Moreover, HKDC1 promoted GC proliferation and migration in vivo. HKDC1 overexpression conferred chemoresistance to cisplatin, oxaliplatin, and 5‐fluorouracil (5‐Fu) onto GC cells. Furthermore, nuclear factor kappa‐B (NF‐κB) inhibitor PS‐341 could attenuate tumorigenesis, metastasis, and drug resistance ability induced by HKDC1 overexpression in GC cells. Our results highlight a critical role of HKDC1 in promoting glycolysis, tumorigenesis, and EMT of GC cells via activating the NF‐κB pathway. In addition, HKDC1‐mediated drug resistance was associated with DNA damage repair, which further activated NF‐κB signaling. HKDC1 upregulation may be used as a potential indicator for choosing an effective chemotherapy regimen for GC patients undergoing chemotherapy.

A spatially mapped gene expression signature for intestinal stem-like cells identifies high-risk precursors of gastric cancer

“…The first recently found that HKDC1 can promote chemoresistance, proliferation and invasion, and epithelial-to-mesenchymal transition through induction of NF-κB. 51 The second study suggests HKDC1 may be pivotal for glycolysis and proliferation in AGS and MKN-45 GC cells. 52 Supporting a relevant role for HKDC1 in carcinogenesis, this gene has been found to promote lung, 53 breast, 54 and biliary 55 cancers.…”

CircVMP1 promotes glycolysis and disease progression by upregulating HKDC1 in colorectal cancer

“…For example, HKDC1 is found to promote glycolysis and disease progression in gastric cancer. 18 Besides, HKDC1 was proven to enhance glycolysis and accelerate endometrial cancer progression. 16 However, in liver cancer, it is reported that HKDC1 promoted liver cancer progression through its interaction with mitochondria instead of enhancing glycolysis.…”

“…As a hexokinase, HKDC1 has been reported to be upregulated and promoted glycolysis in certain cancers. For example, HKDC1 is found to promote glycolysis and disease progression in gastric cancer 18 . Besides, HKDC1 was proven to enhance glycolysis and accelerate endometrial cancer progression 16 .…”

“…Hexokinase domain component 1 (HKDC1), categorized as a putative fifth hexokinase, is a newly discovered protein 15 . However, accumulating evidence demonstrates that HKDC1 promotes glycolysis and cancers progression in endometrial cancer, 16 lung adenocarcinoma, 17 and gastric cancer 18 . In CRC, HKDC1 is demonstrated to upregulate glycolysis 19 .…”

“…15 However, accumulating evidence demonstrates that HKDC1 promotes glycolysis and cancers progression in endometrial cancer, 16 lung adenocarcinoma, 17 and gastric cancer. 18 In CRC, HKDC1 is demonstrated to upregulate glycolysis. 19 Thus, HKDC1 may serve as a potential target for cancer treatment.…”