ETV4 promotes breast cancer cell stemness by activating glycolysis and CXCR4-mediated sonic Hedgehog signaling

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.

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“…Interestingly, among the genes found upregulated in ex vivo skeletal stem/progenitor cells were genes playing cell stemness function such as Trib3 , which confers cell stemness through interaction with beta-catenin and by enhancing Sox2 transcription ( Yu et al, 2019 ; Zhang et al, 2019 ; Lu et al, 2020 ), Slca3 gene, a component of a “consensus gene signature” defining self-renewal of stem cells ( Kim et al, 2014 ) and Ndrg1r a hypoxia induced gene promoting stem-like properties were also upregulated ( Wang et al, 2017 ). Several others genes playing similar function such as Pdpn, Egr1 , Etv4 , and Ackr/CXCR7 were unregulated in ex vivo skeletal stem/progenitor cells as well ( Merino et al, 2015 ; Sakakini et al, 2016 ; Tang et al, 2016 ; Park et al, 2017 ; Danielyan et al, 2020 ; Zhu et al, 2021 ). In addition, genes encoding growth factors, signaling components, masters of collagen biosynthesis (Pcolce2) ( Baicu et al, 2012 ) and several collagen proteins as well were also part of the upregulation profile ( Figures 5C,D ).…”

“…Among them, the procollagen C-endopeptidase enhancer (PCOLCE), an extra-cellular matrix (ECM) remodeling molecule involved in collagen biosynthesis ( Baicu et al, 2012 ), and a repertoire of genes encoding collagen proteins components of the ECM. Of relevance, several genes encoding growth factors and stem cells factors/determinants controlling stemness ( Kim et al, 2014 ; Kuruvilla et al, 2015 ; Ghaleb and Yang, 2017 ; Park et al, 2017 ; Yu et al, 2019 ; Zhang et al, 2019 ; Lu et al, 2020 ; Zhu et al, 2021 ), self-renewal ( Sakakini et al, 2016 ) and cell motility/migration ( Danielyan et al, 2020 ; Yu et al, 2021 ) were also found upregulated significantly in ex vivo skeletal stem/progenitor cells. These findings suggest that ex vivo skeletal stem/progenitor cells “orchestrate” a compelling repertoire of components known to play an important role for the homeostasis of a stem cell “niche,” the microenvironment maintaining the stem cell in an undifferentiated and self-renewing state ( Scadden, 2006 ; Brizzi et al, 2012 ; Birbrair, 2017 ).…”

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“…Metastatic breast cancer has a high mortality, especially for late-stage patients [ 67 ]. Despite early detection and improved therapeutic regimens, drug resistance, relapse and metastasis still occur and result in significant reduction in the survival of breast cancer patients [ 68 ]. CXCR4 receptor and its ligand CXCL12 play a crucial role in the metastasis of various cancer types including breast cancer [ 69 ].…”

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“…reported that ETV4, as a pivotal transcription factor, regulates gene expression associated with glycolysis. In the presence of loss of ETV4, glycolytic enzymes, such as HK2 and LDHA, and glucose uptake are inhibited ( 42 ). Liu et al.…”