Inhibition of UBE2C Promotes Parkin‐Mediated K63‐Linked Ubiquitination of TOP2A to Induce Senescence and Increase Sensitivity of Doxorubicin in Breast Cancer

Abstract Breast cancer is now the second most commonly diagnosed cancer and the most common female malignancy. Chemotherapy‐based adjuvant therapy after surgery and neoadjuvant therapy before surgery are cornerstones of breast cancer treatment. Doxorubicin is one of the most commonly used anthracycline chemotherapy treatments for breast cancer; however, doxorubicin resistance is a major barrier to its clinical use. Therefore, there is an urgent need to discover new targets to overcome doxorubicin resistance in breast cancer. Ubiquitin‐conjugating enzyme 2C (UBE2C) is an E2 ubiquitin‐conjugating enzyme that catalyzes the assembly of K11‐linked ubiquitin chains. In recent years, dysregulation of UBE2C has been implicated in a variety of cancers, including breast cancer; however, the underlying mechanisms remain unclear. In the present study, UBE2C was found to be markedly upregulated in breast cancer and transcriptionally regulated by FOXM1. Inhibition of UBE2C suppressed proliferation and induced senescence in breast cancer cells. Moreover, the inhibition of UBE2C promoted Parkin‐mediated K63‐linked ubiquitination of TOP2A, leading to its proteasomal degradation and thus sensitizing breast cancer cells to doxorubicin. The study reveals that UBE2C is a critical regulator of breast cancer cell proliferation, senescence, and sensitivity to doxorubicin.