Cyclin D1 depletion induces DNA damage in mantle cell lymphoma lines

Abstract

Elevated cyclin D1 (CCND1) expression levels in mantle cell lymphoma (MCL) are associated with aggressive clinical manifestations related to chemoresistance, but little is known about how this important proto-oncogene contributes to the resistance of MCL. Here, we showed that RNA interference-mediated depletion of CCND1 increased caspase-3 activities and induced apoptosis in the human MCL lines UPN-1 and JEKO-1. In vitro and xenotransplant studies revealed that the toxic effect of CCND1 depletion in MCL cells was likely due to increase in histone H2AX phosphorylation, a DNA damage marker. DNA fiber analysis suggested deregulated replication initiation after CCND1 depletion as a potential cause of DNA damage. Finally, in contrast to depletion or inhibition of cyclin-dependent kinase 4, CCND1 depletion increased chemosensitivity of MCL cells to replication inhibitors hydroxyurea and cytarabine. Our findings have an important implication for CCND1 as a potential therapeutic target in MCL patients who are refractory to standard chemotherapy.

Keywords:

• Chemoresistance
• cyclin D1
• DNA damage
• mantle cell lymphoma
• replication stress

Acknowledgements

We thank Drs Louis M. Staudt and Yandan Yang for MCL cell lines and the Tet-repressor expressing UPN-1 cells, and Dr Jeremy Stark for feedback and technical advice. We also thank Dr Ravi Bhatia for helpful discussions. This work was supported in part by the National Cancer Institute of the National Institute of Health [grant number P30CA033572].

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article at http://dx.doi.org/10.1080/10428194.2016.1198958.