Sex-Determining Region Y Box 4 Is a Transforming Oncogene in Human Prostate Cancer Cells

Abstract

Prostate cancer is the most commonly diagnosed noncutaneous neoplasm and second most common cause of cancerrelated mortality in western men. To investigate the mechanisms of prostate cancer development and progression, we did expression profiling of human prostate cancer and benign tissues. We show that the SOX4 is overexpressed in prostate tumor samples compared with benign tissues by microarray analysis, real-time PCR, and immunohistochemistry. We also show that SOX4 expression is highly correlated with Gleason score at the mRNA and protein level using tissue microarrays. Genes affected by SOX4 expression were also identified, including BCL10, CSF1, and NcoA4/ARA70. TLE-1 and BBC3/PUMA were identified as direct targets of SOX4. Silencing of SOX4 by small interfering RNA transfection induced apoptosis of prostate cancer cells, suggesting that SOX4 could be a therapeutic target for prostate cancer. Stable transfection of SOX4 into nontransformed prostate cells enabled colony formation in soft agar, suggesting that, in the proper cellular context, SOX4 can be a transforming oncogene. (Cancer Res 2006; 66(8): 4011-9)

Identification of SOX4 target genes using phylogenetic footprinting-based prediction from expression microarrays suggests that overexpression of SOX4 potentiates metastasis in hepatocellular carcinoma

“…Although the importance of several SOX family proteins is well characterized in vertebrate developmental processes (Bowles et al, 2000), fully defined SOX target genes are few. There are four known SOX4 targets, p56 lck , CD2, TLE1 and PUMA but the SOX4 binding motifs for only p56 lck and CD2 are known (Wotton et al, 1995;McCracken et al, 1997;Liu et al, 2006). This study is the first to report 31 experimentally confirmed direct target genes for SOX4 in one publication.…”

“…Empirical evidence suggested that SOX4 plays an important function in liver tumor metastasis as RNAi knockdown reduced HCC cell migration, invasion and intrahepatic metastasis in an orthotopic liver cancer model. This SOX4 function also seems to operate during breast cancer metastasis (Tavazoie et al, 2008) but not in other human cancer types (Aaboe et al, 2006;Liu et al, 2006;Pramoonjago et al, 2006). This suggests that SOX4 has diverse activities across various human cancers and that these are likely to be cell context-dependent, involving differential target activation.…”

“…Fourteen genes with sixfold higher expression in the T3 tissues were identified and these were enriched with adhesion molecules (NRCAM, CD24, CTHRC1 and ROBO1) and transcription factors (FOXQ1, CDCA7 L, MYBL2 and SOX4); thus, these genes are candidate genes for direct involvement in tumor metastasis (Figures 1a and b). Overexpression of SOX4 has been shown to promote apoptosis in bladder carcinoma (Aaboe et al, 2006); in contrast, RNAi knockdown of SOX4 induces apoptosis in adenoid cystic carcinoma and prostate cancer (Liu et al, 2006;Pramoonjago et al, 2006). This suggests that the SOX4 molecular activity during caracinogenesis is influenced by additional factors that are enriched in a tissuespecific manner.…”

“…SOX4 is absent in adult normal livers (Hunt and Clarke, 1999), hence it is not involved in normal liver functions. Recently, overexpression of SOX4 has been found to be associated with several human cancer types (Aaboe et al, 2006;Liu et al, 2006;Pramoonjago et al, 2006). Although SOX4 was the first 'classical' transcription factor identified with separable DNA-binding and transactivation domains among the SOX family members, information on its target genes is scanty.…”

Developing and characterization of single chain variable fragment (scFv) antibody against frizzled 7 (Fzd7) receptor

“…17 Recently, the overexpression of SOX4 has been reported in several tumors, including prostate cancer, breast cancer and colon cancer. [18][19][20] It has well documented that SOX4 stabilizes b-catenin, and increases Wnt signaling pathway in many types of cancers. 21 Taking together it seems that SOX4 transcription factor plays an vital role in Wnt signaling pathways in TNBC 14,22 Aberrant Fzd7 expression is found in different types of human cancers.…”