# Up-Regulation of Non-Homologous End-Joining by MUC1

## TL;DR

This study shows that MUC1 increases DNA repair in pancreatic cancer cells, making them resistant to treatment, but this can be targeted with specific inhibitors.

## Contribution

The paper reveals a novel mechanism by which MUC1 promotes IR resistance through NHEJ enhancement and HR suppression.

## Key findings

- MUC1 overexpression enhances non-homologous end-joining (NHEJ) while partially suppressing homologous recombination (HR).
- MUC1-overexpressed cells are more sensitive to DNA-PK and HDAC1/2 inhibitors.
- The imbalance between NHEJ and HR caused by MUC1 can be targeted for selective cancer cell killing.

## Abstract

Ionizing radiation (IR) and chemotherapy with DNA-damaging drugs such as cisplatin are vital cancer treatment options. These treatments induce double-strand breaks (DSBs) as cytotoxic DNA damage; thus, the DSB repair activity in each cancer cell significantly influences the efficacy of the treatments. Pancreatic cancers are known to be resistant to these treatments, and the overexpression of MUC1, a member of the glycoprotein mucins, is associated with IR- and chemo-resistance. Therefore, we investigated the impact of MUC1 on DSB repair. This report examined the effect of the overexpression of MUC1 on homologous recombination (HR) and non-homologous end-joining (NHEJ) using cell-based DSB repair assays. In addition, the therapeutic potential of NHEJ inhibitors including HDAC inhibitors was also studied using pancreatic cancer cell lines. The MUC1-overexpression enhances NHEJ, while partially suppressing HR. Also, MUC1-overexpressed cancer cell lines are preferentially killed by a DNA-PK inhibitor and HDAC1/2 inhibitors. Altogether, MUC1 induces metabolic changes that create an imbalance between NHEJ and HR activities, and this imbalance can be a target for selective killing by HDAC inhibitors. This is a novel mechanism of MUC1-mediated IR-resistance and will form the basis for targeting MUC1-overexpressed pancreatic cancer.