# E3 ubiquitin ligase FBXW11-mediated downregulation of S100A11 promotes sensitivity to PARP inhibitor in ovarian cancer

## TL;DR

This study shows that FBXW11 makes ovarian cancer cells more sensitive to PARP inhibitors by degrading S100A11, which affects DNA repair.

## Contribution

The novel finding is that FBXW11 promotes PARP inhibitor sensitivity in ovarian cancer by ubiquitinating and degrading S100A11.

## Key findings

- FBXW11 expression increases in ovarian cancer cells treated with PARP inhibitors.
- Low FBXW11 levels correlate with poor prognosis and resistance to PARP inhibitors in high-grade serous ovarian cancer.
- FBXW11 promotes DNA damage by degrading S100A11, enhancing PARP inhibitor effectiveness.

## Abstract

Resistance to poly adenosine diphosphate (ADP)-ribose polymerase inhibitor (PARPi) presents a considerable obstacle in the treatment of ovarian cancer. F-box and tryptophan-aspartic (WD) repeat domain containing 11 (FBXW11) modulates the ubiquitination of growth-and invasion-related factors in lung cancer, colorectal cancer, and osteosarcoma. The function of FBXW11 in PARPi therapy is still ambiguous. In this study, RNA sequencing (RNA-seq) showed that FBXW11 expression was raised in ovarian cancer cells that had been treated with PARPi. FBXW11 was abnormally expressed at low levels in high-grade serous ovarian cancer (HGSOC) tissues, and low levels of FBXW11 were associated with shorter overall survival (OS) and progression-free survival (PFS) in HGSOC patients. Overexpressing FBXW11 made ovarian cancer more sensitive to PARPi, while knocking down FBXW11 made it less sensitive. The four-dimensional (4D) label-free quantitative proteomic analysis revealed that FBXW11 targeted S100 calcium binding protein A11 (S100A11) and promoted its degradation through ubiquitination. The increased degradation of S100A11 led to less efficient DNA damage repair, which in turn contributed to increased PARPi-induced DNA damage. The role of FBXW11 in promoting PARPi sensitivity was also confirmed in xenograft mouse models. In summary, our study confirms that FBXW11 promotes the susceptibility of ovarian cancer cells to PARPi via affecting S100A11-mediated DNA damage repair.

Image 1

•FBXW11 expression increases in ovarian cancer cells treated with olaparib.•LOW FBXW11 expression shows poor prognosis and higher tolerance to PARPi in HGSOC.•FBXW11 increased olaparib-induced DNA damage by promoting S100A11 degradation.•FBXW11 has great potential in the treatment of PARPi in ovarian cancer.

FBXW11 expression increases in ovarian cancer cells treated with olaparib.

LOW FBXW11 expression shows poor prognosis and higher tolerance to PARPi in HGSOC.

FBXW11 increased olaparib-induced DNA damage by promoting S100A11 degradation.

FBXW11 has great potential in the treatment of PARPi in ovarian cancer.