SOX4 Is Essential for Prostate Tumorigenesis Initiated by PTEN Ablation

Abstract

Understanding remains incomplete of the mechanisms underlying initiation and progression of prostate cancer, the most commonly diagnosed cancer in American men. The transcription factor SOX4 is overexpressed in many human cancers, including prostate cancer, suggesting it may participate in prostate tumorigenesis. In this study, we investigated this possibility by genetically deleting Sox4 in a mouse model of prostate cancer initiated by loss of the tumor suppressor Pten. We found that specific homozygous deletion of Sox4 in the adult prostate epithelium strongly inhibited tumor progression initiated by homozygous loss of Pten. Mechanistically, Sox4 ablation reduced activation of AKT and β-catenin, leading to an attenuated invasive phenotype. Furthermore, SOX4 expression was induced by Pten loss as a result of the activation of PI3K-AKT-mTOR signaling, suggesting a positive feedback loop between SOX4 and PI3K-AKT-mTOR activity. Collectively, our findings establish that SOX4 is a critical component of the PTEN-PI3K-AKT pathway in prostate cancer, with potential implications for combination targeted therapies against both primary and advanced prostate cancers.

Amplification of SOX4 promotes PI3K/Akt signaling in human breast cancer

“…However, given that our data demonstrate a clear loss of phosphorylated Akt in the absence of SOX4 expression, but no discernible difference in total Akt, the effect of SOX4 on signaling appears to be upstream of Akt. It was recently reported that SOX4 cooperates with PTEN loss to mediate prostate cancer tumorigenesis [45]; however given that we see a comparable effect on SOX4 -mediated Akt phosphorylation in both PTEN normal and PTEN deleted cells, it is unclear whether this is also true in breast cancer. The potential does exist that SOX4 could mediate PTEN activity.…”

Promoter hypermethylation of SOX11 correlates with adverse clinicopathological features of human prostate cancer

“…Several members of the SOX family have been implicated in prostate carcinogenesis. SOX2, SOX4 and SOX9 demonstrated tumour-promoting role in functional and clinicopathological studies (Zhong et al 2012;Weina & Utikal 2014;Bilir et al 2016). SOX7 and SOX10 appear to have tumour suppressor properties, and both were found to be downregulated in aggressive prostate cancer (Zhong et al 2012).…”

“…; Weina & Utikal ; Bilir et al . ). SOX7 and SOX10 appear to have tumour suppressor properties, and both were found to be downregulated in aggressive prostate cancer (Zhong et al .…”

Histological and Pathological Assessment of miR-204 and SOX4 Levels in Gastric Cancer Patients

“…Numerous studies have found SOX4 plays an oncogenic role in many kinds of human cancers [24–29]. Bilir et al demonstrated that SOX4 promoted tumor initiation and development in prostate cancer [25]. Song et al documented that SOX4 was associated with malignant status of breast cancer [42].…”