TY - JOUR AU - Li, Ni AU - Xue, Wei AU - Yuan, Huairui AU - Dong, Baijun AU - Ding, Yufeng AU - Liu, Yongfeng AU - Jiang, Min AU - Kan, Shan AU - Sun, Tongyu AU - Ren, Jiale AU - Pan, Qiang AU - Li, Xiang AU - Zhang, Peiyuan AU - Hu, Guohong AU - Wang, Yan AU - Wang, Xiaoming AU - Li, Qintong AU - Qin, Jun T1 - AKT-mediated stabilization of histone methyltransferase WHSC1 promotes prostate cancer metastasis PY - 2017/04/03/ AB - Loss of phosphatase and tensin homolog (PTEN) and activation of the PI3K/AKT signaling pathway are hallmarks of prostate cancer (PCa). However, these alterations alone are insufficient for cells to acquire metastatic traits. Here, we have shown that the histone dimethyl transferase WHSC1 critically drives indolent PTEN-null tumors to become metastatic PCa. In a PTEN-null murine PCa model, WHSC1 overexpression in prostate epithelium cooperated with Pten deletion to produce a metastasis-prone tumor. Conversely, genetic ablation of Whsc1 prevented tumor progression in PTEN-null mice. Molecular characterization revealed that increased AKT activity due to PTEN loss directly phosphorylates WHSC1 at S172, preventing WHSC1 degradation by CRL4Cdt2 E3 ligase. Increased WHSC1 expression transcriptionally upregulates expression of RICTOR, a pivotal component of mTOR complex 2 (mTORC2), to further enhance AKT activity. Therefore, the AKT/WHSC1/mTORC2 signaling cascade represents a vicious feedback loop that elicits unrestrained AKT signaling. Furthermore, we determined that WHSC1 positively regulates Rac1 transcription to increase tumor cell motility. The biological importance of a WHSC1-mediated signaling cascade is substantiated by patient sample analysis in which WHSC1 signaling is tightly correlated with disease progression and recurrence. Taken together, our findings highlight a pivotal link between an epigenetic regulator, WHSC1, and key intracellular signaling molecules, AKT, RICTOR, and Rac1, to drive PCa metastasis. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI91144 VL - 127 IS - 4 UR - https://doi.org/10.1172/JCI91144 SP - 1284 EP - 1302 PB - The American Society for Clinical Investigation ER -