The CEBPD transcription factor: a signaling hub for promotion of cancer cell stemness

Authors

• K Balamurugan
• DY Mendoza
• G Summers
• S Sharan
• E Sterneck

Abstract

Cancer stem-like cells (CSCs) have been implicated in metastasis and treatment resistance. Our previous studies showed that the transcription factor CCAAT enhancer binding protein delta (CEBPD) promotes tumor metastasis in a mouse model of mammary tumorigenesis (MMTV-Neu). Mechanistically, we have correlated CEBPD’s prometastatic activity to inhibition of the F-box protein FBXW7, a bona fide tumor suppressor, which leads to hypoxia adaptation and proinflammatory signaling. We hypothesized that CEBPD-mediated inhibition of FBXW7 also promotes cell stemness. We tested this hypothesis using a variety of tumor cell lines, patient-derived cell lines, and primary tumor tissues. Here we show that CEBPD augments hypoxia- and IL-6-induced expression of mesenchymal markers, CSCs and the generation of mammospheres by human breast cancer and glioblastoma cells. Silencing of CEBPD delayed the outgrowth of MCF-7 xenograft tumors with reduced levels of the CD44+:CD24- CSC population, and decreased angiogenesis. Mechanistic studies in culture models show that CEBPD is expressed in CSCs and connects and amplifies both hypoxia and inflammation pathways to increase Notch1 activity. Additionally, we found that CEBPD directly activates the expression of stemness associated genes such as OCT4, Sox2, KLF4, Myc, Nanog, CD44 and CD133. Taken together, this study provided novel insights into the molecular mechanism that promote cancer cell stemness, and identified a central role for CEBPD in integrating HIF-1α, IL-6/STAT3, and Notch1 signaling, while also activating expression of stemness factors (relevant for breast and glioblastoma, and possibly other cancer types). Furthermore, these results strongly suggest that pharmacological inhibition of CEBPD signaling may effectively target CSCs.

Scientific Focus Area: Stem Cell Biology

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