Abstract
BackgroundChemoresistance is a critical risk problem for breast cancer treatment. However, mechanisms by which chemoresistance arises remains to be elucidated. The expression of T-box transcription factor 15 (TBX-15) was found downregulated in some cancer tissues. However, role and mechanism of TBX15 in breast cancer chemoresistance is unknown. Here we aimed to identify the effects and mechanisms of TBX15 in doxorubicin resistance in breast cancer.MethodsAs measures of Drug sensitivity analysis, MTT and IC50 assays were used in DOX-resistant breast cancer cells. ECAR and OCR assays were used to analyze the glycolysis level, while Immunoblotting and Immunofluorescence assays were used to analyze the autophagy levels in vitro. By using online prediction software, luciferase reporter assays, co-Immunoprecipitation, Western blotting analysis and experimental animals models, we further elucidated the mechanisms.ResultsWe found TBX15 expression levels were decreased in Doxorubicin (DOX)-resistant breast cancer cells. Overexpression of TBX15 reversed the DOX resistance by inducing microRNA-152 (miR-152) expression. We found that KIF2C levels were highly expressed in DOX-resistant breast cancer tissues and cells, and KIF2C was a potential target of miR-152. TBX15 and miR-152 overexpression suppressed autophagy and glycolysis in breast cancer cells, while KIF2C overexpression reversed the process. Overexpression of KIF2C increased DOX resistance in cancer cells. Furthermore, KIF2C directly binds with PKM2 for inducing the DOX resistance. KIF2C can prevent the ubiquitination of PKM2 and increase its protein stability. In addition, we further identified that Domain-2 of KIF2C played a major role in the binding with PKM2 and preventing PKM2 ubiquitination, which enhanced DOX resistance by promoting autophagy and glycolysis.ConclusionsOur data identify a new mechanism by which TBX15 abolishes DOX chemoresistance in breast cancer, and suggest that TBX15/miR-152/KIF2C axis is a novel signaling pathway for mediating DOX resistance in breast cancer through regulating PKM2 ubiquitination and decreasing PKM2 stability. This finding suggests new therapeutic target and/or novel strategy development for cancer treatment to overcome drug resistance in the future.
Highlights
Chemoresistance is a critical risk problem for breast cancer treatment
TBX15 overexpression abrogates breast cancer DOX resistance by suppressing glycolysis and autophagy To identify the mechanisms of DOX resistance in breast cancer cells, using bioinformatics methods we found potential 21 transcription factors (TFs) (ZEB1, TEAD1, NFAT5, MEOX2, TWST1, MAFF, RFX2, MEF2C, EGR2, EBF1, KLF14, JUN, MEIS2, NR3C2, BACH2, BHLHE41, NR3C1, TBX15, MSX1, LHX6, ETV5) that were downregulated in both breast cancer tissues and DOX-resistant breast cancer cells in the JASPER database (Fig. 1A)
A Venn diagram showing the intersection of genes identified in The Cancer Genome Atlas (TCGA) that are downregulated in breast cancer, genes downregulated in MCF7/ADR cells (GSE76540 database), and from TFs identified in the JASPER database
Summary
Chemoresistance is a critical risk problem for breast cancer treatment. mechanisms by which chemoresistance arises remains to be elucidated. The expression of T-box transcription factor 15 (TBX-15) was found downregulated in some cancer tissues. Role and mechanism of TBX15 in breast cancer chemoresistance is unknown. We aimed to identify the effects and mechanisms of TBX15 in doxorubicin resistance in breast cancer. Resection and chemotherapy are used to improve survival, yet many patients develop chemoresistance which often leads to the recurrence of the disease. Doxorubicin (DOX) is an anthracycline chemotherapy agent that is effective in treating a wide range of malignancies, including breast cancer [4]. It is important to identify new mechanisms that circumvent DOX chemoresistance to improve breast cancer therapy and patient survival. We found expression levels of TBX15 were downregulated in DOX-resistant breast cancer tissues, and were strongly correlated with miR-152 levels
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