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PTEN loss and PI3K/AKT signaling pathway activation are hallmarks of prostate cancer.However,this alteration alone is insufficient to enable the cells acquiring metastatic traits.Here we show that histone dimethyltransferase WHSC1 is a critical determinant driving indolent PTEN-null tumor to metastatic PCa.Molecular characterizations revealed that activated AKT directly phosphorylates WHSC1 to prevent its degradation mediated by CRL4Cdt2 E3 ligase.Increased WHSC1 expression transcriptionally up-regulates the expression of Rictor,a pivotal component of mTOR complex 2(mTORC2)to enhance AKT activity.Therefore,AKT-WHSC1-mTORC2 signal cascade represents a vicious positive feedback loop to elicit the unstrained AKT signaling as well as high WHSC1 protein level.Furthermore,we demonstrate that WHSC1 positively regulates Rac1 transcription to potentiate the indolent tumors developing into metastatic cancer.The biological significance of WHSC1 mediated signal cascade is substantiated by patient sample analysis,in which WHSC1 signaling is tightly correlated with disease progression and recurrence.Most importantly,WHSC1 together with PTEN or phospho-AKT level enhance the prognostic accuracy in patients.Taken together,our findings highlight a new pivotal link between an epigenetic regulator,WHSC1 and key intracellular signaling molecules,AKT,Rictor and Rac1,to drive full malignant progression of PCa,which will facilitate the development of molecular prognostic tools for clinical diagnosis.