Abstract
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.
Highlights
Breast cancer is the most commonly occurring cancer and remains the leading cause of cancer-related deaths in women worldwide[1,2]
We report that ETV4 is a critical transcription factor for metabolic rewiring in cancer cells, it promotes the transcription of hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA), two enzymes indispensable for efficient glycolytic flux
Since ETV4 is a coactivator of hypoxia-inducible factor signaling[38], we hypothesized that ETV4 could serve as a regulator of glycolytic metabolism to regulate cancer cell growth
Summary
Breast cancer is the most commonly occurring cancer and remains the leading cause of cancer-related deaths in women worldwide[1,2]. Cancer stem cells (CSCs), a Official journal of the Cell Death Differentiation Association. Zhu et al Cell Death Discovery (2021)7:126 incompletely clarified how the key properties of BCSCs are regulated. Metabolic reprogramming is a hallmark of cancer, characterized by a shift toward glycolysis even in the presence of oxygen (Warburg effect)[13,14,15]. Regulation of glycolytic enzymes is an efficient way to orchestrate cellular glycolysis. HIF-1α, c-Myc, and p53 are well-established glycolysis-associated transcription factors by directly activating or suppressing transcription of glycolytic genes[14]. SIX1 was identified as a key transcription factor promoting glycolytic enzymes expression[25]. Despite that several transcription factors involved in glycolysis regulation have been identified, transcriptional regulation of this metabolic shift needs further elucidation
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