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AIbZIP/CREB3L4 Promotes Cell Proliferation via the SKP2-p27 Axis in Luminal Androgen Receptor Subtype Triple-Negative
Taichi Ito1, Atsushi Saito1, Yasunao Kamikawa1
1Department of Biochemistry, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Molecular Cancer Research : MCR
|January 18, 2024
Summary
Androgen-induced basic leucine zipper (AIbZIP) drives proliferation in luminal androgen receptor (LAR) subtype triple-negative breast cancer (TNBC). Inhibiting AIbZIP suppresses cancer cell growth by upregulating p27 and downregulating SKP2.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Triple-negative breast cancer (TNBC) presents a significant global health challenge with limited therapeutic options.
- The luminal androgen receptor (LAR) subtype of TNBC is particularly aggressive and requires novel therapeutic targets.
- Androgen-induced basic leucine zipper (AIbZIP), also known as CREB3L4, is implicated in cancer progression.
Purpose of the Study:
- To investigate the functional role of AIbZIP in the proliferation of LAR subtype TNBC.
- To elucidate the molecular mechanisms by which AIbZIP influences cell cycle progression in TNBC.
- To identify AIbZIP as a potential therapeutic target for LAR subtype TNBC.
Main Methods:
- siRNA-mediated knockdown of AIbZIP in MFM223 and MDAMB453 LAR subtype TNBC cell lines.
- Cell proliferation assays to assess the impact of AIbZIP depletion.
- Flow cytometry to analyze cell cycle distribution (G1-S transition).
- Western blotting to evaluate the expression levels of cell cycle regulatory proteins, including p27 and SKP2.
- Investigation of the ubiquitin-proteasome system's role in p27 regulation.
Main Results:
- Depletion of AIbZIP significantly suppressed proliferation in LAR subtype TNBC cells.
- AIbZIP knockdown led to the inhibition of G1-S phase transition.
- Specifically, p27 expression was upregulated in AIbZIP-depleted cells.
- This p27 upregulation was attributed to decreased protein degradation mediated by the ubiquitin-proteasome system, involving SKP2 upregulation.
Conclusions:
- AIbZIP is a key regulator of cell proliferation in the LAR subtype of TNBC.
- AIbZIP influences cell cycle progression through a novel pathway involving p27 and SKP2.
- AIbZIP represents a potential therapeutic target for combating LAR subtype TNBC progression.
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