# Cyclin C promotes pancreatic developmentand suppresses cancer initiation by maintenance of the autophagy-lysosome pathway

## TL;DR

Cyclin C supports pancreatic health by regulating autophagy and preventing cancer, and its absence increases sensitivity to proteasome inhibitors.

## Contribution

Cyclin C's dual role in pancreatic development and cancer suppression via autophagy and mitochondrial function is newly identified.

## Key findings

- Cyclin C is essential for autophagy-related gene transcription in mouse embryonic fibroblasts.
- Loss of Ccnc in the pancreas leads to islet atrophy, acinar cell damage, and accelerated precancerous lesions.
- Ccnc−/− cells with autophagy deficiency are hypersensitive to proteasome inhibitors.

## Abstract

Cyclin C (CCNC) is a component of the mediator complex that regulates gene transcription. In stressed cells, cyclin C also translocates to the mitochondria to induce fission and stimulate programmed cell death. The present study found that cyclin C is required for autophagy lysosome pathway gene transcription in mouse embryonic fibroblasts. In vivo, pancreatic ablation of Ccnc caused islet atrophy and acinar cell damage. However, Ccnc pancreatic ablation caused more dramatic phenotypes than autophagy mutants alone, including increased mortality and accelerated precancerous lesion formation. Previous studies found that autophagy-deficient pancreatic cells expressing oncogenic Kras undergo Tp53-dependent cell death. However, KrasG12D;Ccnc−/− pancreata did not undergo cell death, suggesting a role for the mitochondrial cyclin C function. Finally, loss of CCNC activity rendered cells hypersensitive to proteasome inhibitors. These findings identify multiple roles for cyclin C in promoting pancreatic health and suggest a new strategy to target pancreatic neoplasms by inhibiting proteasome function.

•Cyclin C (Ccnc) is required for transcription of autophagy-related genes•Ccnc is required for normal β cell development preventing hyperglycemia in mice•Ccnc ablation coupled with Ras2G12V expression results in ADM and PanIN lesions•Autophagy deficiency renders Ccnc−/− cells hypersensitive to proteasome inhibitors

Cyclin C (Ccnc) is required for transcription of autophagy-related genes

Ccnc is required for normal β cell development preventing hyperglycemia in mice

Ccnc ablation coupled with Ras2G12V expression results in ADM and PanIN lesions

Autophagy deficiency renders Ccnc−/− cells hypersensitive to proteasome inhibitors

Biological sciences; Cell biology; Cancer