It is well known that insulin can activate both PI3K/Akt pathway, which is responsible for glucose uptake, and MAPK pathway, which is crucial for insulin resistance formation. But, it is unclear exactly how the two pathways coordinate to regulate insulin sensitivity upon hyperinsulinism stress of type 2 diabetes mellitus (T2DM). Here, we show that an early response transcription factor Egr‐1 could tilt the signalling balance by blocking PI3K/Akt signalling through PTEN and augmenting Erk/MAPK signalling through GGPPS, resulting in insulin resistance in adipocytes. Egr‐1, PTEN and GGPPS are upregulated in the fat tissue of T2DM patients and db/db mice. Egr‐1 overexpression in epididymal fat induced systematic insulin resistance in wild‐type mice, and loss of Egr‐1 function improved whole‐body insulin sensitivity in diabetic mice, which is mediated by Egr‐1 controlled PI3K/Akt and Erk/MAPK signalling balance. Therefore, we have revealed, for the first time, the mechanism by which Egr‐1 induces insulin resistance under hyperinsulinism stress, which provides an ideal pharmacological target since inhibiting Egr‐1 can simultaneously block MAPK and augment PI3K/Akt activation during insulin stimulation.

One of the most important characteristics of type 2 diabetes is insulin resistance, during which the patients normally experienced hyperinsulinism stress that would alter insulin signal transduction in insulin target tissues. We have previously found that early growth responsive gene-1 (Egr-1), a zinc finger transcription factor, is highly expressed in db/db mice and in the fat tissue of individuals with type 2 diabetes. In this report, we found that chronic exposure to hyperinsulinism caused persistent Erk/MAPK activity in adipocytes and enhanced insulin resistance in an Egr-1-dependent manner. An elevation in Egr-1 augmented Erk1/2 activation via geranylgeranyl diphosphate synthase (GGPPS). Egr-1-promoted GGPPS transcription increased Ras prenylation and caused Erk1/2 activation. The sustained activation of Erk1/2 resulted in the phosphorylation of insulin receptor substrate-1 at Serine 612. Phosphorylation at this site impaired insulin signaling in adipocytes and reduced glucose uptake. The loss of Egr-1 function, knockdown of GGPPS, or inhibition of Erk1/2 activity in insulin-resistant adipocytes restored insulin receptor substrate-1 tyrosine phosphorylation and increased insulin sensitivity. Our results suggest a new mechanism by which the Egr-1/GGPPS/Erk1/2 pathway is responsible for insulin resistance during hyperinsulinism. This pathway provides a new therapeutic target for increasing insulin sensitivity: inhibiting the function of Egr-1.

In the present study, we first examined the expression of USP39 protein using tissue array containing 90 colorectal cancer (CRC) tissues and 9 clinical samples, and observed that it has significantly higher expression in cancer tissues as compared to the corresponding adjacent normal tissues. Also, we tested USP39 expression level in four CRC cancer cell lines and identified that it indeed had higher expression in all these CRC cell lines. In addition, its knockdown inhibited not only the cell growth of SW480 and HT29 cells, but also the cell migration and invasion. Further analysis of its molecular mechanism suggested that the expression of four crucial proteins of Wnt/β-catenin pathway, including β-catenin, TCF4, MMP2 and MMP9 was reduced as a result of USP39 knockdown. Taken together, all these findings demonstrated that USP39 protein plays an important role in the growth and metastasis of colorectal cancer mainly through Wnt/β-catenin pathway.