Colon cancer is an aggressive epithelial tumor type encompassing cancer stem cells (CSCs) that not only contribute to its grow at the primary site but also to its malignant progression, resistance to chemotherapy, and distant metastases thus underlying poor patient outcomes. We have previously reported that significant upregulation of the gene encoding for the Fos-related antigen-1 (FOSL1) upon pro-inflammatory cytokine interleukin-6 (IL-6)-driven epithelial-to-mesenchymal transition (EMT) in colon cancer. However, the underlying molecular and cellular mechanism through which inflammatory cytokines like IL6 regulate CSCs plasticity during colon cancer onset and progression development remain unclear. Here, we show that IL-6 enhanced the stemness, drug resistance and metastasis of colon cancer cells by upregulation and deacetylation of the transcription factor FRA1. Ectopic expression of FRA1 in colon cancer cells induced stem-like properties and metastasis, while its knockdown suppressed these IL-6 induced effects. IL-6 enhanced FRA1 transcription through the STAT3 pathway. Also, we show that FRA1 directly interacts with the promoter of the CSC transcriptional factor Nanog and transactivates its expression to modulate colon cancer stemness. Furthermore, deacetylation of lysine 116 (K116) in FRA1 was essential for its activity on Nanog transcription. Preliminary analyses with Trichostatin A (TSA), an inhibitor of histone deacetylases (HDACs) I and II, but not nicotinamide (NAM), an inhibitor of the sirtuin (SIRT) family of deacetylases, showed that some member of the HDACs family might be responsible for FRA1 deacetylation. Finally, we examined the expression of IL6/STAT3-pY(705)/FRA1/k116ac/Nanog/HDACs/β-catenin in 120 paraffin-embedded human colon cancer tissues by immunohistochemistry (IHC). We found that while FRA1 was mainly localized in the nucleus of cancer cells, K116ac of FRA1 was present both in the nucleus and cytoplasm and showed a low level of Lys116 acetylation in the FRA1 nuclear fraction. Moreover, analysis of patient-derived colon cancer samples supported the clinical relevance of the IL-6/STAT3/FRA1/Nanog axis in contributing to the increased colon cancer stemness and metastasis. We propose that a transcriptional regulatory cross-talk between pro-inflammatory and cancer stemness signaling pathways drives the reprogramming of colon cancer cells to CSCs thus promoting progression towards malignancy and distant metastasis. Combinations of anti-IL6 therapies with HDACs inhibitors may offer a potential novel approach for colon cancer treatment. Keywords: Inflammation, cancer cell stemness, transcription, deacetylation, colon cancer
Citation Format: Tingyang Wang, Jimin Shao. Pro-inflammatory cytokine IL-6 induces the upregulation and deacetylation of FRA-1, thus promoting colon cancer stemness and aggressiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1997.