Zhu Tao, Zheng Juyan, Zhuo Wei, Pan Pinhua, Li Min, Zhang Wei, Zhou Honghao, Gao Yang, Li Xi, Liu Zhaoqian
Departments of Clinical Pharmacology and Respiratory Medicine, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
Institute of Clinical Pharmacology, Engineering Research Center for applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, China.
Cell Death Discov. 2021 May 29;7(1):126. doi: 10.1038/s41420-021-00508-x.
Cancer stem cells (CSCs) are a major cause of tumor treatment resistance, relapse and metastasis. Cancer cells exhibit reprogrammed metabolism characterized by aerobic glycolysis, which is also critical for sustaining cancer stemness. However, regulation of cancer cell metabolism rewiring and stemness is not completely understood. Here, we report that ETV4 is a key transcription factor in regulating glycolytic gene expression. ETV4 loss significantly inhibits the expression of HK2, LDHA as well as other glycolytic enzymes, reduces glucose uptake and lactate release in breast cancer cells. In human breast cancer and hepatocellular carcinoma tissues, ETV4 expression is positively correlated with glycolytic signaling. Moreover, we confirm that breast CSCs (BCSCs) are glycolysis-dependent and show that ETV4 is required for BCSC maintenance. ETV4 is enriched in BCSCs, its knockdown and overexpression suppresses and promotes breast cancer cell stem-like traits, respectively. Mechanistically, on the one hand, we find that ETV4 may enhance glycolysis activity to facilitate breast cancer stemness; on the other, ETV4 activates Sonic Hedgehog signaling by transcriptionally promoting CXCR4 expression. A xenograft assay validates the tumor growth-impeding effect and inhibition of CXCR4/SHH/GLI1 signaling cascade after ETV4 depletion. Together, our study highlights the potential roles of ETV4 in promoting cancer cell glycolytic shift and BCSC maintenance and reveals the molecular basis.
癌症干细胞（CSCs）是肿瘤治疗耐药、复发和转移的主要原因。癌细胞表现出以有氧糖酵解为特征的重编程代谢，这对维持癌症干性也至关重要。然而，癌细胞代谢重编程和干性的调控机制尚未完全明确。在此，我们报道ETV4是调节糖酵解基因表达的关键转录因子。ETV4缺失显著抑制乳腺癌细胞中HK2、LDHA以及其他糖酵解酶的表达，降低葡萄糖摄取和乳酸释放。在人乳腺癌和肝癌组织中，ETV4表达与糖酵解信号呈正相关。此外，我们证实乳腺癌症干细胞（BCSCs）依赖糖酵解，并表明ETV4是BCSCs维持所必需的。ETV4在BCSCs中富集，其敲低和过表达分别抑制和促进乳腺癌细胞的干细胞样特性。机制上，一方面，我们发现ETV4可能增强糖酵解活性以促进乳腺癌干性；另一方面，ETV4通过转录促进CXCR4表达来激活Sonic Hedgehog信号通路。异种移植试验验证了ETV4缺失后的肿瘤生长抑制作用以及对CXCR4/SHH/GLI1信号级联的抑制。总之，我们的研究突出了ETV4在促进癌细胞糖酵解转变和BCSCs维持中的潜在作用，并揭示了其分子基础。
