BOP1 confers chemoresistance of triple‐negative breast cancer by promoting CBP‐mediated β‐catenin acetylation

Abstract

Chemoresistance is a major obstacle to the treatment of triple‐negative breast cancer (TNBC), which has a poor prognosis. Increasing evidence has demonstrated the essential role of cancer stem cells (CSCs) in the process of TNBC chemoresistance. However, the underlying mechanism remains unclear. In the present study, we report that block of proliferation 1 (BOP1) serves as a key regulator of chemoresistance in TNBC. BOP1 expression was significantly upregulated in chemoresistant TNBC tissues, and high expression of BOP1 correlated with shorter overall survival and relapse‐free survival in patients with TNBC. BOP1 overexpression promoted, while BOP1 downregulation inhibited the drug resistance and CSC‐like phenotype of TNBC cells in vitro and in vivo. Moreover, BOP1 activated Wnt/β‐catenin signaling by increasing the recruitment of cyclic AMP response element‐binding protein (CBP) to β‐catenin, enhancing CBP‐mediated acetylation of β‐catenin, and increasing the transcription of downstream stemness‐related genes CD133 and ALDH1A1. Notably, treating with the β‐catenin/CBP inhibitor PRI‐724 induced an enhancement of chemotherapeutic response of paclitaxel in BOP1‐overexpressing TNBC cells. These findings indicate that BOP1 is involved in chemoresistance development and might serve as a prognostic marker and therapeutic target in TNBC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

BOP1 Used as a Novel Prognostic Marker and Correlated with Tumor Microenvironment in Pan-Cancer

“…We found that BOP1 mRNA was upregulated in 25 types of cancer and downregulated in LAML and THCA samples. The results were consistent with previous studies in gastric cancer [ 8 ], colorectal cancer [ 10 , 20 ], prostate cancer [ 9 ], triple-negative breast cancer [ 21 ], and hepatocellular carcinoma [ 13 ]. These findings suggested that BOP1 is likely to operate as an oncogene in most tumors.…”

“…The Kaplan–Meier survival analysis showed that increased BOP1 expression was correlated with poor OS in nine tumors. Similarly, it was previously reported that BOP1 expression is related to shorter survival period in patients with prostate carcinoma [ 9 ], triple-negative breast cancer [ 21 ], gastric cancer [ 8 ], and hepatocellular carcinoma [ 24 ], and BOP1 promotes the development of these cancers. Moreover, BOP1 expression might be used as a potential prognostic marker in patients with tumor metastases [ 9 , 21 ].…”

“…Similarly, it was previously reported that BOP1 expression is related to shorter survival period in patients with prostate carcinoma [ 9 ], triple-negative breast cancer [ 21 ], gastric cancer [ 8 ], and hepatocellular carcinoma [ 24 ], and BOP1 promotes the development of these cancers. Moreover, BOP1 expression might be used as a potential prognostic marker in patients with tumor metastases [ 9 , 21 ]. By contrast, the opposite was found with a relationship between BOP1 expression and prognosis in LGG patients.…”

The interaction of canonical Wnt/β-catenin signaling with protein lysine acetylation

“…Moreover, dependent on HATs as mentioned above, multiple molecules are involved in modulating β-catenin acetylation. For instance, Li et al found that blocking proliferation 1 (BOP1) can initiate β-catenin acetylation that is dependent on CBP to strengthen the drug resistance of breast cancer [ 26 ]. Forkhead box protein P1 (FOXP1) has been proven to activate this signaling by increasing β-catenin acetylation in different biological processes [ 27 , 28 ].…”

The CK1δ/ϵ-Tip60 Axis Enhances Wnt/β-Catenin Signaling via Regulating β-Catenin Acetylation in Colon Cancer

“…CREPT could enhance the association of p300 with β-catenin, thus promoting p300-mediated β-catenin acetylation and stabilization ( 50 ). Li et al reported that block of proliferation 1 (BOP1) could increase Wnt/β-catenin signaling by enhancing CBP recruitment to β-catenin, thus promoting β-catenin acetylation and activation ( 51 ). A recent study showed that Bcl-3 could enhance the Wnt signaling cascade by maintaining the acetylation of β-catenin at K 49 in colorectal cancer ( 40 ).…”