The online version of this article (https://doi.org/10.1186/s13046-018-0888-y) contains supplementary material, which is available to authorized users.
Bo Wang and Ping Fan contributed equally to this work.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal tumor types worldwide. BET inhibitors display anti-tumor activity in pancreatic cancer, however the cells often develop resistance after a long-term treatment and the underlying molecular basis is not fully understood.
Drug screening assay in Fructose-1, 6-biphosphatase (FBP1) knockdown or overexpressing pancreatic cancer cells was performed. Tumor cell motility, FBP1 protein and mRNA changes were investigated after BET inhibitors treatment. The interaction between TRIM28 and FBP1 after BET inhibitors treatment was examined by Co-immunoprecipitation (IP) and GST pull-down. The relationship between FBP1 and c-Myc was examined by western blot, RT-qPCR and immunohistochemistry (IHC).
The expression of FBP1 protein increased the sensitivity of pancreatic cancer cells to JQ1. Furthermore, we showed that JQ1 stabilized FBP1 protein level by disrupting the interaction between FBP1 and TRIM28 in pancreatic cancer cells. Moreover, we demonstrated that FBP1 promoted c-Myc degradation through disrupting the ERK-c-Myc axis.
FBP1 modulates the sensitivity of pancreatic cancer cells to BET inhibitors by decreasing the expression of c-Myc. These findings highlight FBP1 could be used as a therapeutic niche for patient-tailored therapies.
Additional file 1: Figure S1. BRD2, BRD3 or BRD4 make no effect on the expression of FBP1. Table S2. Sequences for shRNAs. (ZIP 272 kb)13046_2018_888_MOESM1_ESM.zip
Mazur PK, Herner A, Mello SS, Wirth M, Hausmann S, Sanchez-Rivera FJ, Lofgren SM, Kuschma T, Hahn SA, Vangala D, et al. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat Med. 2015;21:1163–71. CrossRefPubMedPubMedCentral
Bian B, Bigonnet M, Gayet O, Loncle C, Maignan A, Gilabert M, Moutardier V, Garcia S, Turrini O, Delpero JR, et al. Gene expression profiling of patient-derived pancreatic cancer xenografts predicts sensitivity to the BET bromodomain inhibitor JQ1: implications for individualized medicine efforts. EMBO Mol Med. 2017;9:482–97. CrossRefPubMedPubMedCentral
Jiang SH, Li J, Dong FY, Yang JY, Liu DJ, Yang XM, Wang YH, Yang MW, Fu XL, Zhang XX, et al. Increased serotonin signaling contributes to the Warburg effect in pancreatic tumor cells under metabolic stress and promotes growth of pancreatic tumors in mice. Gastroenterology. 2017;153:277–91. e219 CrossRefPubMed
Jin X, Yan Y, Wang D, Ding D, Ma T, Ye Z, Jimenez R, Wang L, Wu H, Huang H. DUB3 promotes BET inhibitor resistance and Cancer progression by deubiquitinating BRD4. Mol Cell. 2018;
Yan Y, An J, Yang Y, Wu D, Bai Y, Cao W, Ma L, Chen J, Yu Z, He Y, et al. Dual inhibition of AKT-mTOR and AR signaling by targeting HDAC3 in PTEN- or SPOP-mutated prostate cancer. EMBO Mol Med. 2018;10
Bos JL. Ras oncogenes in human cancer: a review. Cancer Res. 1989;49:4682–9. PubMed
Togel L, Nightingale R, Chueh AC, Jayachandran A, Tran H, Phesse T, Wu R, Sieber OM, Arango D, Dhillon AS, et al. Dual targeting of Bromodomain and Extraterminal domain proteins, and WNT or MAPK signaling, inhibits c-MYC expression and proliferation of colorectal Cancer cells. Mol Cancer Ther. 2016;15:1217–26. CrossRefPubMed
Bandukwala HS, Gagnon J, Togher S, Greenbaum JA, Lamperti ED, Parr NJ, Molesworth AM, Smithers N, Lee K, Witherington J, et al. Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors. Proc Natl Acad Sci U S A. 2012;109:14532–7. CrossRefPubMedPubMedCentral
- FBP1 loss contributes to BET inhibitors resistance by undermining c-Myc expression in pancreatic ductal adenocarcinoma
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