SATB2 Induces Malignant Transformation and Cancer stem Cell Characteristics, and Inhibition of Its Expression Reverses Drug Resistance in Mesothelioma

SATB2 (special AT-rich binding protein-2) is a chromatin modifier and epigenetic regulator that regulates gene expression by acting as a transcriptional co-factor. The objective of this paper was to examine whether overexpression of the SATB2 gene is sufficient to induce cellular transformation in a human mesothelial cell line in vitro, and inhibition of its expression in cancer stem cells (CSCs) reverses drug resistance in mesothelioma. SATB2 was highly expressed in human mesothelioma (MPM) cell lines, but not in Met5A cells. Overexpression of the SATB2 gene in Met5A cells led to malignant transformation and stemness (induction of stem cell markers and pluripotency-maintenance factors), as evidenced by colony formation in soft agar and spheroid formation in suspension culture. By comparison, Met5A cells (Met5A/empty vector) did not form colonies and spheroids. Furthermore, overexpression of SATB2 in Met5A cells led to increased cell motility, migration, and invasion. SATB2 overexpression also resulted in the induction of EMT-related transcription factors in Met5A/SATB2 cDNA cells compared to those in Met5A/Empty Vector cells. Inhibition of SATB2 by shRNA in the MPM cell line attenuated cell growth, EMT, and stem cell-like characteristics. ChIP assay revealed SATB2 binding to the promoters of Bcl2, XIAP, KLF4, cMyc, Nanog, and Sox2. These data indicate that SATB2 can regulate several cellular functions by modulating the expression of genes involved in transformation, pluripotency, cell survival, proliferation, and EMT. Inhibition of SATB2 expression in CSCs reversed drug-resistance to cisplatin and pemetrexed by suppressing the expression of Oct4 and Sox2. In conclusion, SATB2 can be considered a therapeutic target in MPM, and inhibiting SATB2 in combination with chemotherapy may be a viable option for MPM treatment.