UBE2K promotes breast cancer growth by ubiquitinating and degrading STUB1 to regulate the PKA/CREB1 signaling pathway, forming a feedback loop

Breast cancer (BC) remains one of the major threats to women's health in the 21st century, due to its high incidence and mortality rates. Ubiquitin-conjugating enzymes, as members of the ubiquitin-proteasome system, are responsible for numerous cellular physiological processes. However, ubiquitin-conjugating enzymes may also play unexpected roles in other physiological activities, such as phosphorylation, lactylation, and even methylation. The physiological function of the ubiquitin-conjugating E2 enzyme UBE2K in BC remains unknown. As a result, we looked into UBE2K's physiological role in the malignant development of BC. A combination of RT-qPCR, Transwell migration assays, Western blotting, and CCK-8 analysis was employed to confirm the upregulation of UBE2K in BC cells and to assess its role in promoting cell proliferation and migration. Furthermore, using chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays, we identified and validated CREB1 as a transcription factor for UBE2K for the first time. We discovered that UBE2K regulates the physiological processes of BC cells via the STUB1/PKA/CREB1/p-CREB1 axis. Moreover, functional rescue experiments ultimately displayed that UBE2K promotes the malignant progression of BC cells by via STUB1/PKA/CREB1/p-CREB1 axis. In conclusion, the UBE2K/CREB1 positive feedback loop promotes the development of BC, indicating that UBE2K could be a viable therapeutic target for anti-BC. • For the first time, UBE2K was verified to be highly expressed in breast cancer cell lines. • For the first time, UBE2K was confirmed to promote the proliferation and migration of breast cancer cell lines. • Our study reveals that UBE2K activates the PKA/CREB1/p-CREB1 signaling pathway to promote the proliferation and migration of BC cells via enhancing STUB1 ubiquitination.