Abstract A17: The CEBPD transcription factor: A signaling hub for promotion of cancer cell stemness

Abstract

Abstract 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) (Balamurugan et al., EMBO J, 2010). Here we show that CEBPD serves as a signaling hub, which integrates and amplifies signaling pathways that promote stemness in breast cancer and glioblastoma as well as in embryonic carcinoma stem cells. This work identifies a mechanism by which hypoxia and inflammation promote cancer stem-like cells (CSCs), which are implicated in tumor progression, metastasis, and therapy resistance. We have shown in our earlier studies that CEBPD promotes inflammatory signaling and hypoxia adaptation by inhibiting the expression of the F-box protein FBXW7, a bona fide tumor suppressor (Balamurugan et al., EMBO J 2010; Nature Communications 2013). Because FBXW7 can target the stem cell factor Notch for degradation, we hypothesized that CEBPD can promote cell stemness. We tested this hypothesis using a variety of established breast and glioblastoma tumor cell lines/xenografts, primary mouse mammary tumor cells and tissues, recent patient-derived glioblastoma cell lines, as well as embryonic stem/cancer cell lines. Deletion or depletion of CEBPD reduced the number of stem cells as determined by surface markers, sphere formation, limiting dilution xenografts, and by expression of stemness genes. Mechanistic studies in culture models show that CEBPD is expressed in CSCs and connects and amplifies both hypoxia (HIF-1) and inflammation (IL-6/STAT3) pathways to increase Notch1 activity and cell stemness. Furthermore, we found that CEBPD also directly activates the expression of stemness associated genes such as OCT4, Sox2, KLF4, Myc, Nanog, CD44 and CD133. Taken together, this study provides novel insights into the molecular mechanisms that promote cancer cell stemness, and identifies a central role for CEBPD in integrating HIF-1α, IL-6/STAT3, and Notch1 signaling, while also activating expression of stemness factors. These results strongly suggest that pharmacological inhibition of CEBPD signaling may effectively target CSCs. Citation Format: Balamurugan Kuppusamy, Daniel Mendoza-Villaneuva, Glenn Summers, Shikha Sharan, Esta Sterneck. The CEBPD transcription factor: A signaling hub for promotion of cancer cell stemness. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A17.