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A Functional Genomic Screen Identifies the Deubiquitinase USP11 as a Novel Transcriptional Regulator of ERα in Breast Cancer

Dwane, Lisa ; O'Connor, Aisling E ; Das, Sudipto ; Moran, Bruce ; Mulrane, Laoighse ; Pinto-Fernandez, Adan ; Ward, Elspeth ; Blümel, Anna M ; Cavanagh, Brenton L and Mooney, Brian , et al. (2020) In Cancer Research 80(22). p.5076-5088
Abstract

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 antiendocrine 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 DUBs identified USP11 as a regulator of ERα transcriptional activity, which was further validated... (More)

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 antiendocrine 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 DUBs 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, 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 (KD) cells in the presence of estradiol. RNA sequencing in LCC1 USP11-KD cells revealed significant suppression of cell-cycle-associated and ERα target genes, phenotypes that were not observed in LCC9 USP11-KD, antiendocrine-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 (ERα+) 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+ breast cancer. SIGNIFICANCE: A newly identified role for USP11 in ERα transcriptional activity represents a novel mechanism of ERα regulation and a pathway to be exploited for the management of ER-positive breast cancer.

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Contribution to journal
publication status
published
subject
keywords
Breast Neoplasms/chemistry, Cell Line, Tumor, Deubiquitinating Enzymes/drug effects, Estradiol/pharmacology, Estrogen Antagonists/pharmacology, Estrogen Receptor alpha/genetics, Female, Gene Silencing, Genes, cdc, Humans, Phenotype, Prognosis, Proteome, Tamoxifen/pharmacology, Thiolester Hydrolases/drug effects, Trans-Activators/physiology
in
Cancer Research
volume
80
issue
22
pages
5076 - 5088
publisher
American Association for Cancer Research Inc.
external identifiers
  • scopus:85100353612
  • pmid:33004351
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-20-0214
language
English
LU publication?
yes
additional info
©2020 American Association for Cancer Research.
id
d7d6cb89-ced7-4ee4-a8a0-9b84478f7ab0
date added to LUP
2023-09-13 07:22:19
date last changed
2024-04-06 00:46:10
@article{d7d6cb89-ced7-4ee4-a8a0-9b84478f7ab0,
  abstract     = {{<p>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 antiendocrine 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 DUBs 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, 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 (KD) cells in the presence of estradiol. RNA sequencing in LCC1 USP11-KD cells revealed significant suppression of cell-cycle-associated and ERα target genes, phenotypes that were not observed in LCC9 USP11-KD, antiendocrine-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 (ERα+) 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+ breast cancer. SIGNIFICANCE: A newly identified role for USP11 in ERα transcriptional activity represents a novel mechanism of ERα regulation and a pathway to be exploited for the management of ER-positive breast cancer.</p>}},
  author       = {{Dwane, Lisa and O'Connor, Aisling E and Das, Sudipto and Moran, Bruce and Mulrane, Laoighse and Pinto-Fernandez, Adan and Ward, Elspeth and Blümel, Anna M and Cavanagh, Brenton L and Mooney, Brian and Dirac, Annette M and Jirström, Karin and Kessler, Benedikt M and Ní Chonghaile, Tríona and Bernards, René and Gallagher, William M and O'Connor, Darran P}},
  issn         = {{1538-7445}},
  keywords     = {{Breast Neoplasms/chemistry; Cell Line, Tumor; Deubiquitinating Enzymes/drug effects; Estradiol/pharmacology; Estrogen Antagonists/pharmacology; Estrogen Receptor alpha/genetics; Female; Gene Silencing; Genes, cdc; Humans; Phenotype; Prognosis; Proteome; Tamoxifen/pharmacology; Thiolester Hydrolases/drug effects; Trans-Activators/physiology}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{22}},
  pages        = {{5076--5088}},
  publisher    = {{American Association for Cancer Research Inc.}},
  series       = {{Cancer Research}},
  title        = {{A Functional Genomic Screen Identifies the Deubiquitinase USP11 as a Novel Transcriptional Regulator of ERα in Breast Cancer}},
  url          = {{http://dx.doi.org/10.1158/0008-5472.CAN-20-0214}},
  doi          = {{10.1158/0008-5472.CAN-20-0214}},
  volume       = {{80}},
  year         = {{2020}},
}