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Resistance to bortezomib in breast cancer cells that downregulate Bim through FOXA1 O‐GlcNAcylation
Author(s) -
Liu Yubo,
Wang Xue,
Zhu Tong,
Zhang Nana,
Wang Lingyan,
Huang Tianmiao,
Cao Yu,
Li Wenli,
Zhang Jianing
Publication year - 2019
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.28376
Subject(s) - bortezomib , downregulation and upregulation , foxa1 , cancer research , apoptosis , proteasome inhibitor , breast cancer , cancer cell , proteasome , cancer , chemistry , biology , medicine , microbiology and biotechnology , biochemistry , multiple myeloma , gene
Bortezomib (BTZ), a well‐established proteasome inhibitor used in the clinical therapy, leads the modulation of several biological alterations and in turn induces apoptosis. Although clinical trials with BTZ have shown promising results for some types of cancers, but not for some others, including those of the breast. The molecular basis of BTZ resistance in breast cancer remains elusive. In the present study, we found that cellular O‐GlcNAc modification was dramatically elevated by BTZ treatment in intrinsic resistant MCF‐7 and T47D cells, but not in sensitive MDA‐MB‐231 cells. A progressive increase in O‐GlcNAcylation characterized the increased acquired resistance of MDA‐MB‐231‐derived cells. We showed that elevated O‐GlcNAc subsequently modified breast cancer related pioneer factor FOXA1 and reduced its protein stability. Further, we demonstrated that FOXA1 attenuation was involved in transcriptional downregulation of proapoptotic Bim and thus suppressed breast cancer cell apoptosis. Finally, the combination of O‐GlcNAc inhibitor L01 to BTZ sensitized resistant cells. Our results have revealed a new regulatory mechanism that involves O‐GlcNAc elevation mediated Bim deficiency, which plays a key role in the apoptotic dysregulation and BTZ resistance in breast cancer cells.