Abstract 5737: YAP1 and COX2 converge to regulate SOX2 and urothelial cancer stem cells
Authors: Oki Akira , Hahn Noah , Hoque Mohammad 
Published: July 2017

Abstract
Since cancer stem cell (CSC) are resistant to conventional chemotherapies that efficiently eliminate bulk tumor cells, the elimination is indispensable in treating malignant diseases. However, the underlying mechanisms responsible for the urothelial CSC traits remain elusive. The tumor microenvironment reinforces a chronic inflammatory state to support tumor progression by triggering CSCs. In addition, chemotherapy-induced apoptotic cells release COX2-derived PGE2, which in turn promotes CSC expansion. Environmental risk factors, such as arsenic (As), cause chronic inflammation and have been linked to urothelial carcinoma incidence. We previously developed an in vitro stepwise model for urothelial malignant transformation by As exposure in normal urothelial cells line (HUC1), which may reveal the intimate connections between carcinogenesis, chronic inflammation, and CSCs and provide clues to develop novel therapeutic strategies.
As-exposed cells displayed more aggressive phenotype than As-unexposed cells in a time dependent manner. In gene set enrichment analysis of expression array of chronic As-exposed and unexposed cells; EGFR, COX2 and YAP1 were top-ranked oncogenic signature in As-exposed cells. Moreover, As exposure induced malignant stemness properties. In stem cell-specific RT-PCR array, SOX2 has been gradually overexpressed in line with acquired spheroid formation and self-renewal capacities. SOX2 is frequently overexpressed in numerous Urothelial carcinoma (UC) cell lines as well as in As-exposed cells, especially in the spheroid cells. Stable knockdown of SOX2 reduces in vitro CSCs properties and also in vivo tumorigenicity. COX2/PGE2 and YAP1 signaling pathways are required to accelerate SOX2 activity. Mechanistically, COX2/PGE2 signaling induces promoter methylation of let-7 host gene via inducing DNA methyltransferases, resulting in downregulated let-7 expression and subsequent SOX2 expression. On the other hand, YAP1 induces COX2/PGE2 signaling-independent SOX2 expression, and these signaling mutually compensate via negative feedback mechanism of SOX2, indicating that dual blockade of these signaling is indispensable to eradicate urothelial CSCs. The pharmacological inhibition of COX2 and YAP1 elicited long-lasting therapeutic response by subverting CSCs expansion following chemotherapy in both UC cells-derived and patient-derived xenograft models. In basal type UC, EGFR-targeted therapy was effective in line with previous reports, but the acquired resistance is inevitable. We reveal that COX2 and YAP1 signaling determine acquired resistance to treatment with the EGFR inhibitor via SOX2. Thus, our findings indicate that the combined inhibition of YAP1 and COX2/PGE2 signaling could be an effective therapeutic strategy to slow CSC expansion and UC progression.
Note: This abstract was not presented at the meeting.
Citation Format: Akira Oki, Noah Hahn, Mohammad Hoque. YAP1 and COX2 converge to regulate SOX2 and urothelial cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5737. doi:10.1158/1538-7445.AM2017-5737