Upregulation of SOX9 inhibits the growth of human and mouse melanomas and restores their sensitivity to retinoic acid
Thierry Passeron, … , Yoshinori Miyamura, Vincent J. Hearing
Thierry Passeron, … , Yoshinori Miyamura, Vincent J. Hearing
Published March 9, 2009
Citation Information: J Clin Invest. 2009;119(4):954-963. https://doi.org/10.1172/JCI34015.
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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.

Authors

Thierry Passeron, Julio C. Valencia, Takeshi Namiki, Wilfred D. Vieira, Hélène Passeron, Yoshinori Miyamura, Vincent J. Hearing

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Figure 2

SOX9 decreases the proliferation of melanoma cells.

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SOX9 decreases the proliferation of melanoma cells. (A) B16/F10 murine m...
(A) B16/F10 murine melanoma cells were cotransfected with a puromycin resistance vector and either an empty vector (Control) or the SOX9 cDNA (SOX9) and were grown in medium containing puromycin for 15 days. Upper panel: Macroscopic view of the proliferative clones. Middle panels: The same clones at a magnification of ×10. An immunoblot of proteins extracted from those cells using antibodies against SOX9 and GAPDH is shown. (B) A375 human melanoma cells were cotransfected with a puromycin resistance vector and with either an empty vector or the SOX9 cDNA and were grown in medium containing puromycin for 15 days. Upper panel: Macroscopic view of the proliferative clones. Middle panels: The same clones at a magnification of ×10. An immunoblot of proteins extracted from those cells using antibodies against SOX9 and GAPDH is shown. (C) Relative proliferation of SOX9-transfected cells compared with the control for B16/F10, SK-Mel28, A375, and Mel Juso melanoma cell lines. *P < 0.001. (D) SOX9 induces melanoma cell arrest in the G1 phase. B16/F10 and A375 melanoma cells were transduced with SOX9 lentivirus or with GFP lentivirus as a control and then were selected with blasticidin. After 5 days, the cells were stained with propidium iodide, and the cell cycle was studied using FACS analysis. Percentages of cells in G1 are indicated. G1/(S + G2), ratio of cells in G1 to cells in S plus G2.