A functional genomic screen identifies the deubiquitinase USP11 as a novel transcriptional regulator of ERα in breast cancer.
Dwane L., O'Connor AE., Das S., Moran B., Mulrane L., Pinto-Fernandez A., Ward E., Blümel AM., Cavanagh BL., Mooney B., Dirac AM., Jirström K., Kessler BM., Ní Chonghaile T., Bernards R., Gallagher WM., O'Connor DP.
Approximately 70% of breast cancers express estrogen receptor α (ERα) and depend on this key transcriptional regulator for proliferation and differentiation. While patients with this disease can be treated with targeted anti-endocrine agents, drug resistance remains a significant issue, with almost half of patients ultimately relapsing. Elucidating the mechanisms that control ERα function may further our understanding of breast carcinogenesis and reveal new therapeutic opportunities. Here we investigated the role of deubiquitinases (DUB) in regulating ERα in breast cancer. An RNAi loss-of-function screen in breast cancer cells targeting all DUB identified USP11 as a regulator of ERα transcriptional activity, which was further validated by assessment of direct transcriptional targets of ERα. USP11 expression was induced by estradiol (E2), an effect that was blocked by tamoxifen and not observed in ERα-negative cells. Mass spectrometry revealed a significant change to the proteome and ubiquitinome in USP11 knockdown cells in the presence of E2. RNA sequencing in LCC1 USP11 knockdown cells revealed significant suppression of cell cycle-associated and ERα target genes, phenotypes that were not observed in LCC9 USP11 knockdown, anti-endocrine resistant cells. In a breast cancer patient cohort coupled with in silico analysis of publicly available cohorts, high expression of USP11 was significantly associated with poor survival in ERα-positive patients. Overall, this study highlights a novel role for USP11 in the regulation of ERα activity, where USP11 may represent a prognostic marker in ERα-positive breast cancer.