Abstract
Disease aggressiveness remains a critical factor to the progression of prostate cancer. Transformation of epithelial cells to mesenchymal lineage, associated with the loss of E-cadherin, offers significant invasive potential and migration capability. Recently, Special AT-rich binding protein (SATB1) has been linked to tumor progression. SATB1 is a cell-type restricted nuclear protein, which functions as a tissue-specific organizer of DNA sequences during cellular differentiation. Our results demonstrate that SATB1 plays significant role in prostate tumor invasion and migration and its nuclear localization correlates with disease aggressiveness. Clinical specimen analysis showed that SATB1 was predominantly expressed in the nucleus of high-grade tumors compared to low-grade tumor and benign tissue. A progressive increase in the nuclear levels of SATB1 was observed in cancer tissues compared to benign specimens. Similarly, SATB1 protein levels were higher in a number of prostate cancer cells viz. HPV-CA-10, DU145, DUPro, PC-3, PC-3M, LNCaP and C4-2B, compared to non-tumorigenic PZ-HPV-7 cells. Nuclear expression of SATB1 was higher in biologically aggressive subclones of prostate cancer cells with their respective parental cell lines. Furthermore, ectopic SATB1 transfection conferred increased cell motility and invasiveness in immortalized human prostate epithelial PZ-HPV-7 cells which correlated with the loss of E-cadherin expression. Consequently, knockdown of SATB1 in highly aggressive human prostate cancer PC-3M cells inhibited invasiveness and tumor growth in vivo along with increase in E-cadherin protein expression. Our findings demonstrate that SATB1 has ability to promote prostate cancer aggressiveness through epithelial-mesenchymal transition.
Highlights
Prostate cancer is the second leading cause of cancer-related death among men in the United States, with nearly 33,720 deaths occurred in the year 2011 [1]
Since Special AT-rich binding protein 1 (SATB1) is a nuclear protein and promotes a transcriptionally active chromatin structure by interacting with AT-rich DNA sequences, upregulated in cancer, we determined the levels of this protein in cytosol and nuclear fraction in benign and tumor specimens obtained from same individual
SATB1 overexpression has been correlated with invasive behavior, metastatic phenotype and poor prognosis in gastric cancers and its mechanistic role has been demonstrated in breast cancer [25,26]
Summary
Prostate cancer is the second leading cause of cancer-related death among men in the United States, with nearly 33,720 deaths occurred in the year 2011 [1]. Poor prognosis of prostate cancer is associated with the aggressiveness of tumor cells which endows them with increased ability to intravasate into the vascular and lymphatic compartments, metastasize to distant sites, and cause recurrence even after definitive therapies like surgery and radiation [2,3]. The loss of E-cadherin expression is a hallmark of EMT [7,8]. Loss of E-cadherin expression is commonly associated with tumor invasiveness, metastasis and poor prognosis in various human cancers including prostate cancer [8,9]. Identification of proteins that cause molecular reprogramming of EMT could lead to their identification as prognostic biomarkers and therapeutic targets, thereby enabling the development of novel strategies to reduce prostate cancer aggressiveness
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