Metabolic reprogramming has emerged as a defining feature of many cancer types and alteration of lipid metabolism has been increasingly recognized as a hallmark of cancer cells. It is now well documented that various tumors and their precursor lesions, including prostate cancer, undergo exacerbated endogenous fatty acid biosynthesis (de novo lipogenesis) irrespective of the levels of extracellular lipids [1]. Continuous de novo lipogenesis provides cancer cells with membrane building blocks, signaling lipid molecules and post-translational modifications of proteins to support rapid cell proliferation [2]. Although the expression and activity of many key enzymes involved in de novo fatty acid synthesis, such as ATP citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), Stearoyl-CoA desaturase 1 (SCD1) and fatty acid synthase (FASN), are upregulated and associated with poor clinical outcomes in various types of cancers [3,4], mechanisms underlying the increased lipogenesis in cancers are not completely understood.

Protein kinase C (PKC) is a family of serine/threonine kinases that can be activated by diacylglycerol (DAG), a phospholipid, and Ca2+ (depending on the isoform). Several of the known PKC isoforms have been implicated in the numerous biological functions such as cell growth, differentiation, apoptosis, transformation and cancer [5,6]. PKCε, an oncogenic member of the novel PKC family, is abnormally high expressed and associated with poor clinical outcomes in numerous epithelial tumors, including prostate cancer [[6], [7], [8]]. For prostate cancer, prostate-specific PKCε overexpression in mice leads to prostatic preneoplastic lesions that evolve to overt invasive adenocarcinoma in concomitant with the loss of the tumor suppressor phosphatase and tensin homolog deleted on chromosome ten (PTEN) [9]. Moreover, overexpression of PKCε in prostate gives rise to formation of pre-neoplastic lesions in transgenic mouse model, whereas genetic ablation of PKCε inhibits development of prostate cancer and bone metastasis [10,11]. Our previous data also demonstrated that PKCε mediates protein kinase D3 (PKD3) kinase activity and nuclear localization and contributes to growth and survival of prostate cancer [12]. Interestingly, PKCε promotes tumor aerobic glycolysis and tumor growth through interaction with small mothers against decapentaplegic (SMAD2/3) and increasing glycolytic genes expression in prostate cancer cells [13]. However, whether alterations in PKCε expression or activity affects lipid metabolism is not yet known.

Pyruvate kinase is an enzyme that functions in the glycolytic pathway and catalyzes the last, rate-limiting step of glycolysis by converting phosphoenolpyruvate to pyruvate [14,15]. Current data has been shown that PKM2 is involved in both glycolytic and non-glycolytic pathways and is instrumental in the malignancy of tumor cells, suggesting that it could act as a remarkable therapeutic target [14]. Several studies have revealed that PKM2 can translocate into the nucleus and act as a transcriptional co-factor to promote tumor development [14,16,17]. Intriguingly, PKM2 activates nuclear sterol regulatory element-binding protein 1a (SREBP-1a) target gene expression and lipid biosynthesis by stabilizing SREBP-1a proteins in hepatocellular carcinoma [18]. Down-regulation of PKM2 can reduce the expression of FASN in bladder cancer cells through the AKT/mammalian target of rapamycin (mTOR)/nuclear sterol regulatory element-binding protein 1c（SREBP-1c） axis [19]. However, the biochemical mechanisms governing PKM2 nuclear entry and cancer growth remain unknown.

In the present study, we sought to determine whether PKCε is involved in the activation of PKM2 and lipid metabolism. Our results demonstrated that PKCε promotes phosphorylation of PKM2 at Y105 and nuclear entry, ultimately leading to de novo lipogenesis and prostate cancer cell proliferation and tumor progression.