DNA damage response (DDR) via NKX3.1 expression in prostate cells

Erbaykent-Tepedelen, Burcu; Karamil, Selda; Gonen-Korkmaz, Ceren; Korkmaz, Kemal

doi:10.1016/j.jsbmb.2014.01.001

Cited by 19 publications

(18 citation statements)

References 28 publications

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“…DNA damage induced by doxorubicin was negatively influenced by NKX3-1 expression63. Another study pointed out that IGF1R (14.6-up-regulated in CEM/ADR5000 cells) enhanced the cytotoxicity of doxorubicin in both sensitive and resistant osteosarcoma cells64.…”

Section: Discussionmentioning

confidence: 98%

Genomic and transcriptomic profiling of resistant CEM/ADR-5000 and sensitive CCRF-CEM leukaemia cells for unravelling the full complexity of multi-factorial multidrug resistance

Kadioglu

Cao

Kosyakova

et al. 2016

Sci Rep

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We systematically characterised multifactorial multidrug resistance (MDR) in CEM/ADR5000 cells, a doxorubicin-resistant sub-line derived from drug-sensitive, parental CCRF-CEM cells developed in vitro. RNA sequencing and network analyses (Ingenuity Pathway Analysis) were performed. Chromosomal aberrations were identified by array-comparative genomic hybridisation (aCGH) and multicolour fluorescence in situ hybridisation (mFISH). Fifteen ATP-binding cassette transporters and numerous new genes were overexpressed in CEM/ADR5000 cells. The basic karyotype in CCRF-CEM cells consisted of 47, XX, der(5)t(5;14) (q35.33;q32.3), del(9) (p14.1), +20. CEM/ADR5000 cells acquired additional aberrations, including X-chromosome loss, 4q and 14q deletion, chromosome 7 inversion, balanced and unbalanced two and three way translocations: t(3;10), der(3)t(3;13), der(5)t(18;5;14), t(10;16), der(18)t(7;18), der(18)t(21;18;5), der(21;21;18;5) and der(22)t(9;22). CCRF-CEM consisted of two and CEM/ADR5000 of five major sub-clones, indicating genetic tumor heterogeneity. Loss of 3q27.1 in CEM/ADR5000 caused down-regulation of ABCC5 and ABCF3 expression, Xq28 loss down-regulated ABCD1 expression. ABCB1, the most well-known MDR gene, was 448-fold up-regulated due to 7q21.12 amplification. In addition to well-known drug resistance genes, numerous novel genes and genomic aberrations were identified. Transcriptomics and genetics in CEM/AD5000 cells unravelled a range of MDR mechanisms, which is much more complex than estimated thus far. This may have important implications for future treatment strategies.

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Section: Discussionmentioning

confidence: 98%

Genomic and transcriptomic profiling of resistant CEM/ADR-5000 and sensitive CCRF-CEM leukaemia cells for unravelling the full complexity of multi-factorial multidrug resistance

Kadioglu

Cao

Kosyakova

et al. 2016

Sci Rep

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“…Topoisomerase I is both a key component recruited to the AR transcriptional complex and important for access of DNA repair proteins to sites of DNA damage [8]. NKX3.1 also binds to ATM and recruits it to sites of DNA damage [7,19]. Moreover, NKX3.1 itself undergoes tyrosine phosphorylation within minutes of DNA damage in order to trigger its interaction with ATM [9].…”

Section: Discussionmentioning

confidence: 99%

Nkx3.1 controls the DNA repair response in the mouse prostate

et al. 2015

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BACKGROUNDThe human prostate tumor suppressor NKX3.1 mediates the DNA repair response and interacts with the androgen receptor to assure faithful completion of transcription thereby protecting against TMPRSS2‐ERG gene fusion. To determine directly the effect of Nkx3.1 in vivo we studied the DNA repair response in prostates of mice with targeted deletion of Nkx3.1.METHODSUsing both drug‐induced DNA damage and γ‐irradiation, we assayed expression of γ‐histone 2AX at time points up to 24 hr after induction of DNA damage.RESULTSWe demonstrated that expression of Nkx3.1 influenced both the timing and magnitude of the DNA damage response in the prostate.CONCLUSIONSNkx3.1 affects the DNA damage response in the murine prostate and is haploinsufficient for this phenotype. Prostate 76:402–408, 2016. © 2015 The Authors. The Prostate published by Wiley Periodicals, Inc.

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“…Regardless, follow-up co-immunoprecipitation experiments showed that overexpressed NKX3.1 readily interacted with endogenous XRCC5/Ku80, XRCC6/Ku70, and PARP1 ( Figure 2B). Interaction of DNA-PK with ectopically expressed NKX3.1 was very recently reported in an independent study 41 . We show here that endogenous NKX3.1 also interacts with XRCC5/Ku80, XRCC6/Ku70, and PARP1 ( Figure 2C).…”

Section: Resultsmentioning

confidence: 67%

Systems analysis of the prostate tumor suppressor NKX3.1 supports roles in DNA repair and luminal cell differentiation

Yang

Chung²,

et al. 2014

F1000Res

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NKX3.1 is a homeobox transcription factor whose function as a prostate tumor suppressor remains insufficiently understood because neither the transcriptional program governed by NKX3.1, nor its interacting proteins have been fully revealed. Using affinity purification and mass spectrometry, we have established an extensive NKX3.1 interactome which contains the DNA repair proteins Ku70, Ku80, and PARP, thus providing a molecular underpinning to previous reports implicating NKX3.1 in DNA repair. Transcriptomic profiling of NKX3.1-negative prostate epithelial cells acutely expressing NKX3.1 revealed a rapid and complex response that is a near mirror image of the gene expression signature of human prostatic intraepithelial neoplasia (PIN). Pathway and network analyses suggested that NKX3.1 actuates a cellular reprogramming toward luminal cell differentiation characterized by suppression of pro-oncogenic c-MYC and interferon-STAT signaling and activation of tumor suppressor pathways. Consistently, ectopic expression of NKX3.1 conferred a growth arrest depending on TNFα and JNK signaling. We propose that the tumor suppressor function of NKX3.1 entails a transcriptional program that maintains the differentiation state of secretory luminal cells and that disruption of NKX3.1 contributes to prostate tumorigenesis by permitting luminal cell de-differentiation potentially augmented by defects in DNA repair.

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DNA damage response (DDR) via NKX3.1 expression in prostate cells

Cited by 19 publications

References 28 publications

Genomic and transcriptomic profiling of resistant CEM/ADR-5000 and sensitive CCRF-CEM leukaemia cells for unravelling the full complexity of multi-factorial multidrug resistance

Genomic and transcriptomic profiling of resistant CEM/ADR-5000 and sensitive CCRF-CEM leukaemia cells for unravelling the full complexity of multi-factorial multidrug resistance

Nkx3.1 controls the DNA repair response in the mouse prostate

Systems analysis of the prostate tumor suppressor NKX3.1 supports roles in DNA repair and luminal cell differentiation

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