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  • Estrogen-dependent activation of NCOA3 couples with p300 and NF-κB to mediate antiapoptotic genes in ER-positive breast cancer cells.

Estrogen-dependent activation of NCOA3 couples with p300 and NF-κB to mediate antiapoptotic genes in ER-positive breast cancer cells.

Discover. Oncology (2023-03-01)
Jun Wang, Zhiyong Zhou
ABSTRACT

Circumvention of apoptosis by the elevation of antiapoptotic proteins is an important cause of carcinogenesis. The induction of antiapoptotic genes, including B-cell CLL/lymphoma 2 (BCL2), BCL2 related protein A1 (BCL2A1), BCL2 like 1 (BCL2L1), BCL2L2, and myeloid cell leukemia 1 (MCL1), has been observed in multiple cancers, including breast cancer. However, the underlying mechanisms of their overexpression are still being investigated. Here, we revealed that BCL2, BCL2A1, BCL2L2, and MCL1 but not BCL2L1 were overexpressed in estrogen receptor (ER)-positive breast cancer cells and clinical biopsies. Stimulation with estrogen in ER-positive cell lines resulted in a dose-dependent increase in BCL2, BCL2A1, BCL2L2, and MCL1 mRNA levels. Molecular investigation revealed that nuclear factor kappa B (NF-κB) recruited histone acetyltransferase p300 and nuclear receptor coactivator 3 (NCOA3) to form a transcriptional complex. This complex docked the promoters of BCL2, BCL2A1, BCL2L2, and MCL1 and activated their expression. Interestingly, estrogen exposure dose-dependently activated NCOA3. Depletion of the NCOA3-p300-NF-κB components or blockage of NCOA3 function with inhibitors (gossypol and bufalin) in ER-positive cells suppressed BCL2, BCL2A1, BCL2L2, and MCL1 expression, while also decreasing cell viability, colony formation, cell invasion, and tumor growth. Collectively, our results demonstrate an upstream signaling that activates four antiapoptotic genes in ER-positive breast cancer cells. Importantly, our results also imply that targeting NCOA3 or blocking the assembly of the NCOA3-p300-NF-κB complex may be promising therapeutic strategies for treating ER-positive breast cancer.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Bufalin
Sigma-Aldrich
Anti-Estrogen Receptor-α antibody produced in rabbit, affinity isolated antibody
Sigma-Aldrich
Protease Inhibitor Cocktail, for use in tissue culture media, DMSO solution