Upregulation of SOX9 inhibits the growth of human and mouse melanomas and restores their sensitivity to retinoic acid

Abstract

Treatments for primary and metastatic melanomas are rarely effective. Even therapeutics such as retinoic acid (RA) that are successfully used to treat several other forms of cancer are ineffective. Recent evidence indicates that the antiproliferative effects of RA are mediated by the transcription factor SOX9 in human cancer cell lines. As we have previously shown that SOX9 is expressed in normal melanocytes, here we investigated SOX9 expression and function in human melanomas. Although SOX9 was expressed in normal human skin, it was increasingly downregulated as melanocytes progressed to the premalignant and then the malignant and metastatic states. Overexpression of SOX9 in both human and mouse melanoma cell lines induced cell cycle arrest by increasing p21 transcription and restored sensitivity to RA by downregulating expression of PRAME, a melanoma antigen. Furthermore, SOX9 overexpression in melanoma cell lines inhibited tumorigenicity both in mice and in a human ex vivo model of melanoma. Treatment of melanoma cell lines with PGD2 increased SOX9 expression and restored sensitivity to RA. Thus, combined treatment with PGD2 and RA substantially decreased tumor growth in human ex vivo and mouse in vivo models of melanoma. The results of our experiments targeting SOX9 provide insight into the pathophysiology of melanoma. Further, the effects of SOX9 on melanoma cell proliferation and RA sensitivity suggest the encouraging possibility of a noncytotoxic approach to the treatment of melanoma.

Transcription Factor SOX9 Promotes Osteosarcoma Cell Growth by Repressing Claudin-8 Expression [Retraction]

“…During endochondral bone formation, SOX9 expression is down-regulated in growth plate chondrocytes (Leung et al 2011). The exact role of SOX9 in carcinogenesis and cancer progression is controversial because both oncogenic and tumor-suppressing functions of SOX9 have been described (Passeron et al 2009;Cai et al 2013;. Furthermore, SOX9 expression is up-regulated in several tumor types, including lung adenocarcinoma, esophageal squamous cell carcinoma and breast cancer (Müller et al 2010;Hong et al 2015;Wang et al 2015).…”

MiniSOX9, a dominant-negative variant in colon cancer cells

“…SOX9 also increases apoptosis in colon tumor cells (Jay et al, 2005) and reduces cell proliferation rate, as illustrated by hyperplasia and dysplasia induced by Sox9 abrogation in the intestine epithelium (Bastide et al, 2007;Zalzali et al, 2008). The anti-proliferative activity of SOX9 was also evidenced in retinoid-treated breast cancer cell lines and melanomas (Afonja et al, 2002;Passeron et al, 2009;Muller et al, 2010). Finally, loss of SOX9 expression and promoter hypermethylation is associated with bladder cancer progression (Aleman et al, 2008).…”

SOX9 accelerates ESC differentiation to three germ layer lineages by repressing SOX2 expression through P21 (WAF1/CIP1)

“…SOX9 has shown several pro-oncogenic properties, including the ability to promote proliferation, to inhibit senescence and to collaborate with other oncogenes in neoplastic transformation (Wang et al, 2008;Jiang et al, 2010;Matheu et al, 2012). But some reports demonstrated that overexpression of SOX9 in human melanoma or human endometrial carcinoma, as well as in chondrocytes, inhibited cell proliferation through P21 expression in cooperation with p53 (Panda et al, 2001;Passeron et al, 2009;Saegusa et al, 2012). Variable outcomes are likely to be correlated with the relative activation of P21.…”