Inhibition of the Acetyltransferases p300 and CBP Reveals a Targetable Function for p300 in the Survival and Invasion Pathways of Prostate Cancer Cell Lines

Santer, Frédéric R.; Höschele, Philipp P.S.; Oh, Su Jung; Erb, Holger H.H.; Bouchal, Jan; Cavarretta, Ilaria T.; Parson, Walther; Meyers, David J.; Cole, Philip A.; Čulig, Zoran

doi:10.1158/1535-7163.mct-11-0182

Cited by 192 publications

(160 citation statements)

References 40 publications

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“…To determine whether inhibition of p300 HAT activity is viable as a therapeutic strategy against cancer, we examined the ability of an existing specifi c inhibitor of p300 HAT, C646 ( 42 ), to suppress the growth of CBP -defi cient lung cancer cells. C646 reduced survival in lung cancer cells carrying deleterious CBP mutations (H1703, H520, and LK2) to a greater extent than in CBP WT cells (A549, H1299, and H157) or cells harboring low-impact mutations (H322; Fig.…”

Section: Sensitivity Of Cbp -Defi Cient Lung Cancer Cell To An Existimentioning

confidence: 99%

Targeting p300 Addiction inCBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation ofMYCExpression

Ogiwara¹,

Sasaki²,

Mitachi³

et al. 2016

Cancer Discovery

146

109

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Loss-of-function mutations in the CBP/CREBBP gene, which encodes a histone acetyltransferase (HAT), are present in a variety of human tumors, including lung, bladder, gastric, and hematopoietic cancers. Consequently, development of a molecular targeting method capable of specifi cally killing CBP-defi cient cancer cells would greatly improve cancer therapy. Functional screening of synthetic-lethal genes in CBP -defi cient cancers identifi ed the CBP paralog p300/EP300 . Ablation of p300 in CBP -knockout and CBP -defi cient cancer cells induced G 1 -S cell-cycle arrest, followed by apoptosis. Genome-wide gene expression analysis revealed that MYC is a major factor responsible for the synthetic lethality. Indeed, p300 ablation in CBP -defi cient cells caused downregulation of MYC expression via reduction of histone acetylation in its promoter, and this lethality was rescued by exogenous MYC expression. The p300-HAT inhibitor C646 specifi cally suppressed the growth of CBP -defi cient lung and hematopoietic cancer cells in vitro and in vivo ; thus p300 is a promising therapeutic target for treatment of CBP -defi cient cancers. SIGNIFICANCE:Targeting synthetic-lethal partners of genes mutated in cancer holds great promise for treating patients without activating driver gene alterations. Here, we propose a "synthetic lethalbased therapeutic strategy" for CBP -defi cient cancers by inhibition of the p300 HAT activity. Patients with CBP -defi cient cancers could benefi t from therapy using p300-HAT inhibitors. Cancer Discov; 6(4); 430-45.

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Section: Sensitivity Of Cbp -Defi Cient Lung Cancer Cell To An Existimentioning

confidence: 99%

Targeting p300 Addiction inCBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation ofMYCExpression

Ogiwara¹,

Sasaki²,

Mitachi³

et al. 2016

Cancer Discovery

146

109

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“…Emerging evidence indicates that inhibition of AR coactivators is an effective antiandrogen therapy (8). Recently, it has become evident that inactivation of p300 inhibits prostate tumorigenesis (9). Therefore, identifying new AR coactivators and elucidating their roles in androgen signaling through AR may provide a critical drug target for therapeutic intervention in PCa.…”

mentioning

confidence: 99%

Inactivation of androgen-induced regulator ARD1 inhibits androgen receptor acetylation and prostate tumorigenesis

Wang

Guo

et al. 2012

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

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Androgen signaling through androgen receptor (AR) is critical for prostate tumorigenesis. Given that AR-mediated gene regulation is enhanced by AR coregulators, inactivation of those coregulators is emerging as a promising therapy for prostate cancer (PCa). Here, we show that the N -acetyltransferase arrest-defect 1 protein (ARD1) functions as a unique AR regulator in PCa cells. ARD1 is up-regulated in human PCa cell lines and primary tumor biopsies. The expression of ARD1 was augmented by treatment with synthetic androgen (R1881) unless AR is deficient or is inhibited by AR-specific siRNA or androgen inhibitor bicalutamide (Casodex). Depletion of ARD1 by shRNA suppressed PCa cell proliferation, anchorage-independent growth, and xenograft tumor formation in SCID mice, suggesting that AR-dependent ARD1 expression is biologically germane. Notably, ARD1 was critical for transcriptionally regulating a number of AR target genes that are involved in prostate tumorigenesis. Furthermore, ARD1 interacted physically with and acetylated the AR protein in vivo and in vitro. Because AR–ARD1 interaction facilitated the AR binding to its targeted promoters for gene transcription, we propose that ARD1 functions as a unique AR regulator and forms a positive feedback loop for AR-dependent prostate tumorigenesis. Disruption of AR–ARD1 interactions may be a potent intervention for androgen-dependent PCa therapy.

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“…In addition, in colon cancer, PRKD1 overexpression negatively influenced motility partly by inhibiting the activity of cofilin (Sundram et al 2014). However, PRKD1 was not regulated by NCOA1 in the AR-negative PC3, a cell line known to have high migratory and invasive capability (Santer et al 2011). The low expression of PRKD1 in PC3 compared with AR-positive cell lines may be the explanation for its high motility.…”

Section: Ncoa1 Regulates Various Cell Migration Pathwaysmentioning

confidence: 97%

“…DuCaP cells were a kind gift from Prof. J A Schalken (Nijmegen, The Netherlands) and were grown in RPMI 1640 containing 10% (v/v) FCS (PAA Laboratories, Pasching, Austria), antibiotics (100 units/mL penicillin; 100 units/mL streptomycin) (Lonza) and 2 mM GlutaMAX (Life Technologies, Thermo Fisher). LAPC4 cells, kindly provided by Dr A Cato (Institute of Toxicology and Genetics, Karlsruhe, Germany), were cultured as mentioned previously (Santer et al 2011). HEK 293FT cells were purchased from Life Technologies and grown according to the manufacturer's protocol.…”

Section: Cell Lines and Reagentsmentioning

confidence: 99%

The AR/NCOA1 axis regulates prostate cancer migration by involvement of PRKD1

Luef

Handle

Kharaishvili

et al. 2016

Endocrine-Related Cancer

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Due to the urgent need for new prostate cancer (PCa) therapies, the role of androgen receptor (AR)-interacting proteins should be investigated. In this study we aimed to address whether the AR coactivator nuclear receptor coactivator 1 (NCOA1) is involved in PCa progression. Therefore, we tested the effect of long-term NCOA1 knockdown on processes relevant to metastasis formation. [ 3 H]-thymidine incorporation assays revealed a reduced proliferation rate in AR-positive MDA PCa 2b and LNCaP cells upon knockdown of NCOA1, whereas AR-negative PC3 cells were not affected. Furthermore, Boyden chamber assays showed a strong decrease in migration and invasion upon NCOA1 knockdown, independently of the cell line's AR status. In order to understand the mechanistic reasons for these changes, transcriptome analysis using cDNA microarrays was performed. Protein kinase D1 (PRKD1) was found to be prominently up-regulated by NCOA1 knockdown in MDA PCa 2b, but not in PC3 cells. Inhibition of PRKD1 reverted the reduced migratory potential caused by NCOA1 knockdown. Furthermore, PRKD1 was negatively regulated by AR. Immunohistochemical staining of PCa patient samples revealed a strong increase in NCOA1 expression in primary tumors compared with normal prostate tissue, while no final conclusion could be drawn for PRKD1 expression in tumor specimens. Thus, our findings directly associate the AR/NCOA1 complex with PRKD1 regulation and cellular migration and support the concept of therapeutic inhibition of NCOA1 in PCa.

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Inhibition of the Acetyltransferases p300 and CBP Reveals a Targetable Function for p300 in the Survival and Invasion Pathways of Prostate Cancer Cell Lines

Cited by 192 publications

References 40 publications

Targeting p300 Addiction inCBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation ofMYCExpression

Targeting p300 Addiction inCBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation ofMYCExpression

Inactivation of androgen-induced regulator ARD1 inhibits androgen receptor acetylation and prostate tumorigenesis

The AR/NCOA1 axis regulates prostate cancer migration by involvement of PRKD1

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