Investigating WDR12 as a Therapeutic Target in Breast Cancer

Breast cancer is the most diagnosed and lethal cancer globally in women. Presently, there is a need for novel targets for the development of improved therapeutics. Data mining through genetic screens suggests that the ribosome biogenesis protein WDR12 is essential for breast cancer cell proliferation. In this study, we characterize the effects of WDR12 knockdown in a panel of breast cancer cells. We show that WDR12 knockdown induces ribosomal RNA (rRNA) processing defects resulting in strong growth inhibition in all breast cancer cells tested, however only a subset of lines displayed short-term cell cycle defects. To further understand the cellular consequences of WDR12 suppression, we investigated the global proteomic landscape and found that WDR12 knockdown results in a perturbation of translational and ribosome biogenesis-related networks. Furthermore, we performed RNA-sequencing to assess the global transcriptional changes upon WDR12 knockdown and found dysregulation of the endoplasmic reticulum (ER) stress response pathway. Finally, we characterized the effect of long-term WDR12 suppression and found that growth inhibition was in part due to cellular senescence. Our results demonstrate that WDR12 is implicated in breast cancer cell growth and senescence, and its suppression may represent a viable therapeutic target for breast cancer.

Department dc:contributor.department

Pharmacology

Year dc:date.issued

2023

Author dc:creator

• Kim, Ji Sup

Advisor dc:contributor.advisor

• Al-awar, Rima

• breast cancer
• drug target
• ribosome biogenesis
• senescence
• WD40 repeat
• WDR12

Statement dc:rights

• Attribution 4.0 International

Licence dc:rights.uri

• http://creativecommons.org/licenses/by/4.0/

Handle dc:identifier.uri

http://hdl.handle.net/1807/128041

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/128041