Abiraterone Acetate Induces CREB1 Phosphorylation and Enhances the Function of the CBP-p300 Complex, Leading to Resistance in Prostate Cancer Cells

Pan, Wenting; Zhang, Zhouwei; Kimball, Hannah; Qu, Fangfang; Berlind, Kyler; Stopsack, Konrad H.; Lee, Gwo‐Shu Mary; Choueiri, Toni K.

doi:10.1158/1078-0432.ccr-20-4391

Cited by 24 publications

(23 citation statements)

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“…The detailed results are provided in SI Appendix , Table S2 . Interestingly, a collection of the genes that are implicated in these signaling pathways, including WNT4 ( 49 ), LRP5 ( 50 ), BRAF ( 51 ), GNA13 ( 52 ), PDPK1 ( 53 ), SPHK1 ( 54 ), PRKCA ( 55 ), and CREB1 ( 56 ), have well-recognized roles in drug resistance. Further genomic profiling of the components of the BRD4/LSD1/NuRD complex showed a significant enrichment of these components at the locus of WNT4 , PDPK1 , LRP5 , and GNA13 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We showed that the BRD4/LSD1/NuRD complex–mediated restriction of super-enhancer activation influences various genes, including WNT4 , LRP5 , BRAF , GNA13 , PDPK1 , SPHK1 , PRKCA , and CREB1 , and impacts several cellular signaling pathways including the PI3K-AKT and WNT pathways. Although these genes have been documented to play important roles in drug resistance ( 49 – 56 ), the PI3K-AKT and WNT pathways are important cellular signaling mechanisms profoundly affecting biological activities such as cell growth and differentiation, transcription, replication, apoptosis, and aging ( 78 , 79 ). It will be interesting in future studies to investigate the regulation of these cellular processes by the BRD4/LSD1/NuRD complex and the biological readouts stemmed from the BRD4/LSD1/NuRD complex–mediated restriction of super-enhancer activation.…”

Section: Discussionmentioning

confidence: 99%

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BRD4-directed super-enhancer organization of transcription repression programs links to chemotherapeutic efficacy in breast cancer

Liu

Han

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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BRD4 is well known for its role in super-enhancer organization and transcription activation of several prominent oncogenes including c-MYC and BCL2. As such, BRD4 inhibitors are being pursued as promising therapeutics for cancer treatment. However, drug resistance also occurs for BRD4-targeted therapies. Here, we report that BRD4 unexpectedly interacts with the LSD1/NuRD complex and colocalizes with this repressive complex on super-enhancers. Integrative genomic and epigenomic analyses indicate that the BRD4/LSD1/NuRD complex restricts the hyperactivation of a cluster of genes that are functionally linked to drug resistance. Intriguingly, treatment of breast cancer cells with a small-molecule inhibitor of BRD4, JQ1, results in no immediate activation of the drug-resistant genes, but long-time treatment or destabilization of LSD1 by PELI1 decommissions the BRD4/LSD1/NuRD complex, leading to resistance to JQ1 as well as to a broad spectrum of therapeutic compounds. Consistently, PELI1 is up-regulated in breast carcinomas, its level is negatively correlated with that of LSD1, and the expression level of the BRD4/LSD1/NuRD complex–restricted genes is strongly correlated with a worse overall survival of breast cancer patients. Together, our study uncovers a functional duality of BRD4 in super-enhancer organization of transcription activation and repression linking to oncogenesis and chemoresistance, respectively, supporting the pursuit of a combined targeting of BRD4 and PELI1 in effective treatment of breast cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

BRD4-directed super-enhancer organization of transcription repression programs links to chemotherapeutic efficacy in breast cancer

Liu

Han

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Zhou et al proposed a mechanism of EP300 downregulation by miR-106b∼25, which increased tolerance to doxorubicin and helped to avoid doxorubicin-induced senescence in breast cancer cells [ 42 ]. In turn, increased activity of EP300 correlated with enhanced resistance to a variety of compounds in prostate cancer [ 43 , 44 , 45 ]. In breast cancer cells, inhibition of acetyltransferase sensitized cancer cells to a variety of chemotherapeutics, by impeding drug efflux and increasing drug accumulation [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Activation of ABCC Genes by Cisplatin Depends on the CoREST Occurrence at Their Promoters in A549 and MDA-MB-231 Cell Lines

Sobczak

Strachowska

Gronkowska

et al. 2022

Cancers

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Although cisplatin-based therapies are common among anticancer approaches, they are often associated with the development of cancer drug resistance. This phenomenon is, among others, caused by the overexpression of ATP-binding cassette, membrane-anchored transporters (ABC proteins), which utilize ATP to remove, e.g., chemotherapeutics from intracellular compartments. To test the possible molecular basis of increased expression of ABCC subfamily members in a cisplatin therapy mimicking model, we generated two cisplatin-resistant cell lines derived from non-small cell lung cancer cells (A549) and triple-negative breast cancer cells (MDA-MB-231). Analysis of data for A549 cells deposited in UCSC Genome Browser provided evidence on the negative interdependence between the occurrence of the CoREST complex at the gene promoters and the overexpression of ABCC genes in cisplatin-resistant lung cancer cells. Pharmacological inhibition of CoREST enzymatic subunits—LSD1 and HDACs—restored gene responsiveness to cisplatin. Overexpression of CoREST-free ABCC10 in cisplatin-resistant phenotypes was caused by the activity of EP300 that was enriched at the ABCC10 promoter in drug-treated cells. Cisplatin-induced and EP300-dependent transcriptional activation of ABCC10 was only possible in the presence of p53. In summary, the CoREST complex prevents the overexpression of some multidrug resistance proteins from the ABCC subfamily in cancer cells exposed to cisplatin. p53-mediated activation of some ABCC genes by EP300 occurs once their promoters are devoid of the CoREST complex.

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“…In colon cancer cells, phosphorylation of CREB1 was induced by norepinephrine to facilitate cell proliferation, migration, and invasion [ 45 ]. Besides, in prostate cancer cells, abiraterone acetate treatment can induce CREB1 phosphorylation, which in turn enhances CBP/p300 activity and lead to alterations in global gene expression and subsequently drug resistance [ 46 ]. Moreover, studies have demonstrated an indispensable role of CREB1 in lipid synthesis in liver and adipose in nonruminants.…”

Section: Discussionmentioning

confidence: 99%

Tuftelin 1 Facilitates Hepatocellular Carcinoma Progression through Regulation of Lipogenesis and Focal Adhesion Maturation

Zhu

Zhou

Ming

et al. 2022

Journal of Immunology Research

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Hepatocellular carcinoma (HCC) is the most common type of primary liver malignancy with poor prognosis worldwide. Emerging evidences demonstrated critical roles of lipid de novo synthesis in HCC progression, yet its regulatory mechanisms are not fully understood. Herein, we found that tuftelin 1 (TUFT1), an acidic phosphorylated glycoprotein with secretory capacity, was significantly upregulated in HCC and had an excellent correlation with patient survival and malignancy features. Through database mining and experimental validation, we found that TUFT1 was associated with fatty acid metabolism and promoted lipid accumulation in HCC cells. Further, we found that TUFT1 can interact with CREB1, a transcription factor for hepatic lipid metabolism, and regulate its activity and the transcriptions of key enzymes for lipogenesis. TUFT1 promoted HCC cell proliferation significantly, which was partially reversed by treatment of an inhibitor of CREB1, KG-501. Moreover, TUFT1 promoted the capacity of HCC cell invasion in vitro, which was likely mediated by its association with zyxin, a zinc-binding phosphoprotein responsible for the formation of fully mature focal adhesions on extracellular matrix. We found that TUFT1 can interact with ZYX and inhibit its expression and recruitments to focal complexes in HCC cells. Collectively, our study uncovered new regulatory mechanisms of TUFT1-mediated lipogenesis, cell proliferation, and invasion.

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Abiraterone Acetate Induces CREB1 Phosphorylation and Enhances the Function of the CBP-p300 Complex, Leading to Resistance in Prostate Cancer Cells

Cited by 24 publications

References 50 publications

BRD4-directed super-enhancer organization of transcription repression programs links to chemotherapeutic efficacy in breast cancer

BRD4-directed super-enhancer organization of transcription repression programs links to chemotherapeutic efficacy in breast cancer

Activation of ABCC Genes by Cisplatin Depends on the CoREST Occurrence at Their Promoters in A549 and MDA-MB-231 Cell Lines

Tuftelin 1 Facilitates Hepatocellular Carcinoma Progression through Regulation of Lipogenesis and Focal Adhesion Maturation

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