The myo-inositol biosynthesis rate-limiting enzyme ISYNA1 suppress the stemness of ovarian cancer

Abstract

AbstractCancer stem cells (CSCs) play a central role in tumor formation, invasion, metastasis, chemoresistance and relapse of ovarian cancer (OC). Here we report myo-inositol biosynthesis rate-limiting enzyme (ISYNA1), as a suppressor of OC and regulate cancer stem-like properties of ovarian cancer cells. The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database results showed that lower ISYNA1 level was correlated with shorter overall survival (OS) in TCGA and GEO database. In GEO database, cancer tissues expressed lower level of ISYNA1 compared to normal tissues, and negative associated with the stemness markers. ISYNA1 deficiency promoting the growth, migration, invasion, and self-renewal capability of ovarian cancer cells. We also found that silencing ISYNA1 in ovarian cancer cells enhance CSC properties including sphere formation, the expression level of stem cell factors such as SOX2, NANOG and OCT4, as well as the expression of CSC markers CD44 and CD133, besides, the aldehyde dehydrogenase (ALDH) activity, CD44+/CD117+expression also be analyzed. In contrast, ectopic overexpression of ISYNA1 suppress cell proliferation, migration, and invasion, decrease the stemness of ovarian cancer cells. In xenograft models, ISYNA1 deficiency significantly increases the tumorgenicity and CSC frequency. In addition, we identified P53 could regulate the expression of ISYNA1, and the myo-inositol addition rescue the stemness increased by ISYNA1 knockdown. In conclusion, these data establish the evidence of ISYNA1 as a suppressor of OC and a regulator of OCSCs, providing insight into potentially targetable pathways for ovarian cancer therapy.