Dataset Information

KCNN4 Promotes the Stemness Potentials of Liver Cancer Stem Cells by Enhancing Glucose Metabolism.

ABSTRACT: The presence of liver cancer stem cells (LCSCs) is one of the reasons for the treatment failure of hepatocellular carcinoma (HCC). For LCSCs, one of their prominent features is metabolism plasticity, which depends on transporters and ion channels to exchange metabolites and ions. The K⁺ channel protein KCNN4 (Potassium Calcium-Activated Channel Subfamily N Member 4) has been reported to promote cell metabolism and malignant progression of HCCs, but its influence on LCSC stemness has remained unclear. Here, we demonstrated that KCNN4 was highly expressed in L-CSCs by RT-PCR and Western blot. Then, we illustrated that KCNN4 promoted the stemness of HC-C cells by CD133⁺CD44⁺ LCSC subpopulation ratio analysis, in vitro stemness transcription factor detection, and sphere formation assay, as well as in vivo orthotopic liver tumor formation and limiting dilution tumorigenesis assays. We also showed that KCNN4 enhanced the glucose metabolism in LCSCs by metabolic enzyme detections and seahorse analysis, and the KCNN4-promoted increase in LCSC ratios was abolished by glycolysis inhibitor 2-DG or OXPHOS inhibitor oligomycin. Collectively, our results suggested that KCNN4 promoted LCSC stemness via enhancing glucose metabolism, and that KCNN4 would be a potential molecular target for eliminating LCSCs in HCC.

SUBMITTER: Fan J

PROVIDER: S-EPMC9266406 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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KCNN4 Promotes the Stemness Potentials of Liver Cancer Stem Cells by Enhancing Glucose Metabolism.

Fan Jing J Tian Ruofei R Yang Xiangmin X Wang Hao H Shi Ying Y Fan Xinyu X Zhang Jiajia J Chen Yatong Y Zhang Kun K Chen Zhinan Z Li Ling L

International journal of molecular sciences 20220623 13

The presence of liver cancer stem cells (LCSCs) is one of the reasons for the treatment failure of hepatocellular carcinoma (HCC). For LCSCs, one of their prominent features is metabolism plasticity, which depends on transporters and ion channels to exchange metabolites and ions. The K<sup>+</sup> channel protein <i>KCNN4</i> (Potassium Calcium-Activated Channel Subfamily N Member 4) has been reported to promote cell metabolism and malignant progression of HCCs, but its influence on LCSC stemnes ...[more]

PMID: 35805963

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Project description:CD44 is a single-pass cell surface glycoprotein that is distinguished as the first molecule used to identify cancer stem cells in solid tumors based on its expression. In this regard, the CD44high cell population demonstrates not only the ability to regenerate a heterogeneous tumor, but also the ability to self-regenerate when transplanted into immune-deficient mice. However, the exact role of CD44 in cancer stem cells remains unclear in part because CD44 exists in various isoforms due to alternative splicing. Methods: Gain- and loss-of-function methods in different models were used to investigate the effects of CD44 on breast cancer stemness. Cancer stemness was analyzed by detecting SOX2, OCT4 and NANOG expression, ALDH activity, side population (SP) and sphere formation. Glucose consumption, lactate secretion and reactive oxygen species (ROS) levels were detected to assess glycolysis. Western blot, immunohistochemical staining, ELISA and TCGA dataset analysis were performed to determine the association of CD44ICD and PFKFB4 with clinical cases. A PFKFB4 inhibitor, 5MPN, was used in a xenograft model to inhibit breast cancer development. Results: In this report, we found that the shortest CD44 isoform (CD44s) inhibits breast cancer stemness, whereas the cleaved product of CD44 (CD44ICD) promotes breast cancer stemness. Furthermore, CD44ICD interacts with CREB and binds to the promoter region of PFKFB4, thereby regulating PFKFB4 transcription and expression. The resultant PFKFB4 expression facilitates the glycolysis pathway (vis-à-vis oxidative phosphorylation) and promotes stemness of breast cancer. In addition, we found that CD44ICD and PFKFB4 expressions are generally up-regulated in the tumor portion of breast cancer patient samples. Most importantly, we found that 5MPN (a selective inhibitor of PFKFB4) suppresses CD44ICD-induced tumor development. Conclusion: CD44ICD promotes breast cancer stemness via PFKFB4-mediated glycolysis, and therapies that target PFKFB4 (e.g., 5MPN therapy) may lead to improved outcomes for cancer patients.

Dataset Information

KCNN4 Promotes the Stemness Potentials of Liver Cancer Stem Cells by Enhancing Glucose Metabolism.

Publications

KCNN4 Promotes the Stemness Potentials of Liver Cancer Stem Cells by Enhancing Glucose Metabolism.

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