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Fbxo22-mediated KDM4B degradation determines selective estrogen receptor modulator activity in breast cancer

Yoshikazu Johmura¹, Ichiro Maeda², Narumi Suzuki¹

¹Division of Cancer Cell Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.

The Journal of Clinical Investigation

|November 13, 2018

Abstract:

The agonistic/antagonistic biocharacter of selective estrogen receptor modulators (SERMs) can have therapeutic advantages, particularly in the case of premenopausal breast cancers. Although the contradictory effects of these modulators have been studied in terms of crosstalk between the estrogen receptor α (ER) and coactivator dynamics and growth factor signaling, the molecular basis of these mechanisms is still obscure. We identify a series of regulatory mechanisms controlling cofactor dynamics on ER and SERM function, whose activities require F-box protein 22 (Fbxo22). Skp1, Cullin1, F-box-containing complex (SCFFbxo22) ubiquitylated lysine demethylase 4B (KDM4B) complexed with tamoxifen-bound (TAM-bound) ER, whose degradation released steroid receptor coactivator (SRC) from ER. Depletion of Fbxo22 resulted in ER-dependent transcriptional activation via transactivation function 1 (AF1) function, even in the presence of SERMs. In living cells, TAM released SRC and KDM4B from ER in a Fbxo22-dependent manner. SRC release by TAM required Fbxo22 on almost all ER-SRC-bound enhancers and promoters. TAM failed to prevent the growth of Fbxo22-depleted, ER-positive breast cancers both in vitro and in vivo. Clinically, a low level of Fbxo22 in tumor tissues predicted a poorer outcome in ER-positive/human epidermal growth factor receptor type 2-negative (HER2-negative) breast cancers with high hazard ratios, independently of other markers such as Ki-67 and node status. We propose that the level of Fbxo22 in tumor tissues defines a new subclass of ER-positive breast cancers for which SCFFbxo22-mediated KDM4B degradation in patients can be a therapeutic target for the next generation of SERMs.

Insights

F-box protein 22 (Fbxo22) is crucial for selective estrogen receptor modulator (SERM) effectiveness in breast cancer. Low Fbxo22 levels predict poor outcomes, suggesting Fbxo22 as a therapeutic target for next-generation SERMs.

Area of Science:

Molecular Biology
Oncology
Biochemistry

Background:

Selective estrogen receptor modulators (SERMs) offer therapeutic potential for premenopausal breast cancers.
The molecular mechanisms underlying SERM efficacy, particularly their contradictory effects, remain unclear.
Understanding estrogen receptor α (ER) and coactivator dynamics is key to deciphering SERM action.

Purpose of the Study:

To elucidate the regulatory mechanisms controlling coactivator dynamics on ER and SERM function.
To investigate the role of F-box protein 22 (Fbxo22) in ER-dependent signaling and SERM response.
To identify Fbxo22 as a potential predictive biomarker and therapeutic target in ER-positive breast cancer.

Main Methods:

Utilized biochemical assays to study the Skp1, Cullin1, F-box-containing complex (SCFFbxo22) and its interaction with ER and lysine demethylase 4B (KDM4B).
Employed cell-based experiments to assess the impact of Fbxo22 depletion on ER transcriptional activity and response to tamoxifen (TAM).
Conducted in vitro and in vivo studies using breast cancer models and analyzed clinical tumor samples for Fbxo22 expression.

Main Results:

SCFFbxo22 mediates the ubiquitylation and degradation of KDM4B complexed with TAM-bound ER, facilitating steroid receptor coactivator (SRC) release.
Fbxo22 depletion leads to ER-dependent transcriptional activation, even with SERM treatment, and abrogates TAM's ability to inhibit tumor growth.
Low Fbxo22 levels in tumor tissues correlate with poorer outcomes in ER-positive/HER2-negative breast cancer patients.

Conclusions:

Fbxo22 is essential for SERM efficacy by regulating ER-cofactor dynamics through KDM4B degradation.
Fbxo22 levels can define a novel subclass of ER-positive breast cancers with distinct therapeutic vulnerabilities.
Targeting SCFFbxo22-mediated KDM4B degradation presents a promising strategy for next-generation SERM therapies.

Read full analysis

Keywords:

Breast cancer Endocrinology Molecular diagnosis Ubiquitin-proteosome system

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