Targeting breast cancer stem cells by novel HDAC3-selective inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Histone deacetylase (HDAC) inhibitors can reduce cancer stem cell (CSC) populations.
• The specific HDAC isoforms and mechanisms responsible for this effect are not fully understood.
• Previous work implicated HDAC8 in regulating CSCs in triple-negative breast cancer (TNBC).

Purpose of the Study:

• To investigate the role of HDAC3 in CSC homeostasis in TNBC.
• To identify the molecular pathway through which HDAC3 affects CSCs.
• To develop novel HDAC3-selective inhibitors for potential therapeutic use.

Main Methods:

• Investigated HDAC3's role in CSCs using molecular biology techniques.
• Analyzed the Akt/GSK3β pathway and β-catenin expression.
• Synthesized and characterized HDAC3-selective inhibitors based on the AR-42 scaffold.
• Evaluated inhibitor efficacy in vitro and in vivo for CSC suppression.

Main Results:

• HDAC3 was found to increase β-catenin expression, promoting CSC homeostasis via the Akt/GSK3β pathway.
• Two novel compounds, 18 and 28, demonstrated high potency and selectivity for HDAC3 inhibition.
• These compounds effectively suppressed the CSC subpopulation in TNBC cells in vitro and/or in vivo.
• Suppression of CSCs was achieved through the downregulation of β-catenin.

Conclusions:

• HDAC3 plays a critical role in maintaining CSCs in TNBC by regulating β-catenin.
• Targeting HDAC3 with selective inhibitors represents a promising therapeutic strategy for TNBC.
• Developed HDAC3-selective inhibitors show potential for clinical application in suppressing CSCs.