CapG promotes resistance to paclitaxel in breast cancer through transactivation of PIK3R1/P50

Abstract

Background: Chemotherapy resistance is a major problem in breast cancer treatment and a leading cause of mortality in breast cancer patients. Biomarkers for chemotherapy resistance is under investigation.Methods: Paclitaxel resistant cells were established and subjected to RNA sequencing. Analysis combined with two additional RNA-seq datasets was conducted. CapG expression in patients with adjuvant chemotherapy was studied in breast cancer resection specimens using IHC and related to pathological response and disease-free survival. Paclitaxel resistance was assessed by half-maximal inhibitory concentrations (IC50) and a mouse xenograft model.Results: Increased expression of actin-binding protein CapG strongly correlated with the resistance to paclitaxel chemotherapy and decreased probability to achieve pathological complete response in breast cancer patients. Overexpressing CapG significantly enhanced paclitaxel resistance in breast cancer cells and xenograft tumors. High CapG level also significantly correlated with shorter relapse-free survival as well as hyper-activation of PI3K/Akt signaling in breast cancer patients. Mechanistically, CapG enhanced PIK3R1 expression which led to increased PI3K/Akt activation. Unexpectedly, CapG was found to bind to the variant-specific promoter of PIK3R1/P50 and directly enhance its transcription. We also identified p300/CBP as a transcriptional coregulator of CapG, which is recruited to PIK3R1 promoter through interaction with CapG, thereby increasing PIK3R1/P50 transcription by enhancing histone H3K27 acetylation. Consistently, inhibiting p300/CBP substantially decreased CapG-dependent upregulation of PIK3R1/P50 and subsequent PI3K/Akt activation, resulting in increased sensitivity to paclitaxel treatment in breast cancer cells.Conclusion: High CapG levels may predict poor paclitaxel response in breast cancer patients. Targeting CapG-mediated hyperactivation of PI3K/Akt pathway may mitigate resistance to chemotherapy in breast cancer.

Paclitaxel’s Mechanistic and Clinical Effects on Breast Cancer

“…Chemoresistance is a major problem of cancer treatment associated with poor response, tumor recurrence, and metastases and represents the leading cause of mortality in BC patients [106,107]. Primary chemoresistance refers to resistance occurring prior to treatment.…”

“…Additionally, increased expression of the actin-binding protein (CapG) promoted PTX resistance in BC cells and xenograft models and was related to the PTX resistance in BC patients through targeting CapG-mediated hyperactivation of the PI3K/Akt pathway [106]. Moreover, increased Y-box protein (YB)-1 levels and decreased EGR1 (early growth response protein 1) mRNA levels correlated with PTX resistance in MDA-MB-231, while a proposed mechanism suggested the biological link between EGR1 and YB-1 and that an increase in YB-1 decreased EGR1 [119].…”

Garcinol—A Natural Histone Acetyltransferase Inhibitor and New Anti-Cancer Epigenetic Drug

“…In contrast, p21 cyclindependent kinase inhibitor (CDKN1A) was upregulated [23]. Other transcriptional factors or oncogenes become overexpressed due to histone acetylation by P300/CBP [23][24][25][26]. HAT-histone acetyltransferase, NK-natural killer cells.…”

Linc00665 Can Predict the Response to Cisplatin-Paclitaxel Neoadjuvant Chemotherapy for Breast Cancer Patients

“…Feng et al suggested that inhibition of PI3K/Akt/mTOR pathway in MCF-7 cells can enhance the chemosensitivity of breast cancer cells to cisplatin by enhancing autophagy and apoptosis ( 21 ). Chi et al demonstrated that CapG has been shown to increase PIK3R1 expression and activate the PI3K/Akt pathway, mediating resistance to paclitaxel in breast cancer patients ( 22 ). Through GSEA analysis, we found that Linc00665 overexpression can activate PI3K/Akt pathway.…”