American Association for Cancer Research
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Figure S2 from Obesity/Type 2 Diabetes-Associated Liver Tumors Are Sensitive to Cyclin D1 Deficiency

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journal contribution
posted on 2023-03-31, 03:48 authored by Chi Luo, Jiaxin Liang, Kfir Sharabi, Maximilian Hatting, Elizabeth A. Perry, Clint D.J. Tavares, Lipika Goyal, Amitabh Srivastava, Marc Bilodeau, Andrew X. Zhu, Piotr Sicinski, Pere Puigserver

Deletion of Cyclin D1 in hepatocytes does not alter the mouse metabolic responses.

Funding

American Diabetes Association

Novartis

Canadian Liver Foundation Hepatology Research

Université de Montréal

NIH

ADA

United States Department of the Air Force

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DFCI Claudia Adams Barr Award

NIDDK

History

ARTICLE ABSTRACT

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/nondiabetic 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 antidiabetic 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. Obesity/diabetes-associated liver tumors are specifically vulnerable to cyclin D1 deficiency and CDK4 inhibition, suggesting that the obese/diabetic environment confers cancer-selective dependencies that can be therapeutically exploited.