Cancers display distinct metabolic states that support cancer cell growth and survival. Aerobic glycolysis known as Warburg effect is highly active in cancer cells and plays a critical role in cancer cell proliferation, migration and metastasis.? It provides not only the energy source, but also building blocks for cancer cell proliferation and survival. Understanding the mechanisms by which cancer cells undergo metabolic reprogramming may offer the potential strategies for cancer therapy. Interestingly, accumulating studies reveal that glycolysis is regulated by diverse growth factor receptor signaling through activation of Akt, which drives the progression of many critical steps involved in glycolysis. Akt serves as a critical oncoprotein by regulating many aspects of biological functions including cell proliferation, survival, cell migration, and metastasis. Importantly, the deregulated Akt pathway is associated with a variety of human cancers, and several mouse models with activated Akt pathway support the role of Akt in cancer development. Akt activity is well-known regulated through its phosphorylation at T308 and S473 by PDK1 and mTORC2, respectively. Although in the last decade the research has been primarily focused on Akt phosphorylation and its role in Akt activation and functions, other posttranslational modifications on Akt have never been reported. Until recently, we unraveled for the first time that Akt undergoes a novel posttranslational modification termed K63-linked ubiquitination, which plays a critical role in Akt membrane recruitment and activation. Interestingly, we found K63-linked ubiquitination of Akt is a common mode that is induced by various growth factor receptors and distinct growth factors utilizes different E3 ligases named Skp2 and TRAF6 for K63-linked ubiquitination and activation of Akt. Importantly, the cancer-associated Akt mutant (Akt E17K) recently identified in a subset of human cancers displays enhanced Akt ubiquitination, in turn contributing to Akt hyperactivation 1, 2, suggesting a potential role of Akt ubiquitination in aberrant Akt activation and cancer development. Our genetic mouse models and xenograft models further support the oncogenic roles of Akt E3 ligases (Skp2 and? in cancer development. Our subsequent studies further identify a deubiquitnaitng enzyme for Akt and reveal the critical role of deubiquitination of Akt in restricting Akt membrane recruitment and activation. Thus, this novel posttranslational modification on Akt reveals an exciting avenue that has advanced our current understandings of how Akt signaling activation is regulated and may have important clinical implications for cancer treatment.
　Given the critical role of Skp2 in cancer progression and metastasis, we have developed a high throughput unbiased approach to screen for a small molecule library with 120,000 compounds and further biochemical and molecular biology approaches allowed to identify a specific Skp2 inhibitor to shut off Skp2 E3 ligase activity thereby leading to inhibiting Akt-mediated glycolysis and cancer stemness. Importantly, we showed that such Skp2 inhibitor displays potent in vitro cell killing effect and in vivo anti-tumor activity by acting through Skp2 inhibition. Our genetic and pharmacologic approaches have provided the proof of principle evidence that targeting Skp2 is a potential strategy for cancer therapy.
　In addition to being regulated by Akt signaling, glycolysis is also orchestrated by hypoxia/HIF-1a signaling. HIF-1a is a key transcription factor in response to hypoxia that induces expression of many proteins involved in glycolysis, angiogenesis, cancer progression and metastasis as well as drug resistance. As aggressive cancers are mostly exposed to the hypoxia microenvironment, targeting hypoxia/HIF-1a signaling is therefore a promising strategy for cancer therapy.? HIF-1a is a highly unstable protein that is polyubiquitinated by E3 liagse VHL and subsequently degraded by the 19S proteasome under normoxic conditions, whereas it is stabilized and translocated to the nucleus to induce its target gene expression in hypoxia conditions. While HIF-1a is generally degraded by VHL-mediated ubiquitination, a recent study suggests that HIF-1a could be degraded by a VHL-independent manner. Notably, we identified a key signaling axis that drives the ubiquitinaton process as a critical step for HIF-1a stability and nuclear enrichment under hypoxia.? Notably we show that targeting this signaling axis impairs HIF-1a signaling, glycolysis and cancer progression and metastasis in mouse tumor models. Our study therefore offers a promising strategy to target those cancers with hyperactivated hypoxia/HIF-1a signaling.