A ketogenic enzyme HMGCS2 drives malignant progression in HER2-negative breast cancer via RAB23-mediated β-catenin/TCF signaling and mediates Apatinib resistance.
Abstract
Background
3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) is the rate-limiting enzyme of ketogenesis. However, its role in breast cancer progression and drug resistance beyond metabolic regulation remains poorly understood. This study investigates the oncogenic function and resistance-promoting mechanism of HMGCS2 in HER2-negative breast cancer (BC) treated with Apatinib.
Methods
Metabolomics and immunohistochemistry on Apatinib-treated clinical samples identified HMGCS2 as a resistance-associated gene. Stable knockdown (sh-HMGCS2) and overexpression (OE-HMGCS2) HER2-negative BC cell lines were established. In vitro functional assays (CCK-8, colony formation, Transwell, wound healing, flow cytometry) and in vivo xenograft models were employed. Proteomics, co-immunoprecipitation, and rescue experiments elucidated the underlying mechanism.
Results
HMGCS2 was significantly overexpressed in Apatinib-resistant tumors. Knockdown of HMGCS2 suppressed proliferation, migration, invasion, and colony formation, induced S-phase arrest and apoptosis, and enhanced Apatinib sensitivity, whereas overexpression exerted opposite effects. In vivo, HMGCS2 knockdown reduced tumor growth. Mechanistically, HMGCS2 physically interacted with RAB23 and activated β-catenin/TCF signaling. RAB23 overexpression partially rescued the effects of HMGCS2 knockdown.
Conclusion
This study revealed that HMGCS2, beyond its canonical ketogenic function, acted as an oncogenic driver in HER2-negative BC through RAB23/β-catenin/TCF signaling. Besides, HMGCS2 represented a potential therapeutic target for overcoming Apatinib resistance.