Obesity/type 2 diabetes-associated liver tumors are sensitive to Cyclin D1 deficiency

Type 2 diabetes, which is mainly linked to obesity, is associated with increased incidence of liver cancer. We have previously found that in various models of obesity/diabetes, hyperinsulinemia maintains heightened hepatic expression of Cyclin D1, suggesting a plausible mechanism linking diabetes and liver cancer progression. Here we show that Cyclin D1 is greatly elevated in human livers with diabetes and is among the most significantly upregulated genes in obese/diabetic liver tumors. Liver-specific Cyclin D1 deficiency protected obese/diabetic mice against hepatic tumorigenesis, whereas lean/non-diabetic mice developed tumors irrespective of Cyclin D1 status. Cyclin D1 dependency positively correlated with liver cancer sensitivity to palbociclib, an FDA-approved CDK4 inhibitor, which was effective in treating orthotopic liver tumors under obese/diabetic conditions. The anti-diabetic drug metformin suppressed insulin-induced hepatic Cyclin D1 expression and protected against obese/diabetic hepatocarcinogenesis. These results indicate that the Cyclin D1-CDK4 complex represents a potential selective therapeutic vulnerability for liver tumors in obese/diabetic patients.