Loss of Krüppel-like factor 9 facilitates stemness in ovarian cancer ascites-derived multicellular spheroids via Notch1/slug signaling.

Abstract

The ascites that develops in advanced OC, both at diagnosis and upon recurrence, is a rich source of multicellular spheroids/aggregates (MCSs/MCAs), which are the major seeds of tumor cell dissemination within the abdominal cavity. However, the molecular mechanism by which specific ascites‐derived tumor cells survive and metastasize remains largely unknown. In this study, we elucidated cancer stem cell (CSC) properties of ascites‐derived MCSs, concomitant with enhanced malignancy, induced EMT, and low KLF9 (Krüppel‐like factor 9) expression, compared with PTCs. KLF9 was also downregulated in OC cell line‐derived spheroids and the CD117+CD44+ subpopulation in MCSs. Functional experiments demonstrated that KLF9 negatively modulated stem‐like properties in OC cells. Mechanistic studies revealed that KLF9 reduced the transcriptional expression of Notch1 by directly binding to the Notch1 promoter, thereby inhibiting the function of slug in a CSL‐dependent manner. Clinically, expression of KLF9 was associated with histological grade and loss of KLF9 predicts poor prognosis in OC.