Obesity/Type 2 diabetes-associated liver tumors are sensitive to cyclin D1 deficiency

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageAmerican English
Pages (from-to)3215-3221
Number of pages7
JournalCancer Research
Volume80
Issue number16
DOIs
StatePublished - 15 Aug 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020 American Association for Cancer Research.

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