A gene signature for a long-term survivor of an atypical teratoid/rhabdoid tumor

Huang, Chiang Ching; Pundy, Tatiana; Patel, Kashyap; Halpern, Abby L.; Grupenmacher, Alex Treiger; Chou, Pauline M.; Bonaldo, Maria de Fátima; Tomita, Tadanori

doi:10.1016/j.cancergen.2014.05.009

Cited by 2 publications

(5 citation statements)

References 23 publications

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“…GE data from these microarray experiments have been previously validated by our group. 1,30,36 Our analysis demonstrated overexpression of PLK4 in RTK, AT/RTs, and additional embryonal brain tumors, when compared with other pediatric brain tumor types and normal brain tissue ( Fig. 2A).…”

Section: Plk4 Is Overexpressed In Mrts Rtk At/rts and Other Embryomentioning

confidence: 74%

“…To explore the pattern of PLK4 expression in rhabdoid tumors, we evaluated the microarray GE data of our collection of 116 samples (Supplementary Table S4). GE data from these microarray experiments have been previously validated by our group …”

Section: Resultsmentioning

confidence: 99%

“…A total of 116 samples were included in the study (Supplementary Table S4). GE profiling was performed using Illumina HT‐12v.4 BeadChip whole‐genome expression arrays (Illumina, USA) …”

Section: Methodsmentioning

confidence: 99%

“…The expression of PLK4 (Hs00179514_m1) was verified by TaqMan GE assays (Thermo Fisher Scientific, USA) using the housekeeping gene GAPDH (Hs02758991_g1) as reference as previously described …”

Section: Methodsmentioning

confidence: 99%

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A functional screening of the kinome identifies the Polo‐like kinase 4 as a potential therapeutic target for malignant rhabdoid tumors, and possibly, other embryonal tumors of the brain

Sredni

Suzuki

Yang

et al. 2017

Pediatric Blood & Cancer

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Purpose: Malignant rhabdoid tumors (MRTs) are deadly embryonal tumors of the infancy. With poor survival and modest response to available therapies, more effective and less toxic treatments are needed. We hypothesized that a systematic screening of the kinome will reveal kinases that drive rhabdoid tumors and can be targeted by specific inhibitors. Methods:We individually mutated 160 kinases in a well-characterized rhabdoid tumor cell line (MON) using lentiviral clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). The kinase that most significantly impaired cell growth was further validated. Its expression was evaluated by microarray gene expression (GE) within 111 pediatric tumors, and functional assays were performed. A small molecule inhibitor was tested in multiple rhabdoid tumor cell lines and its toxicity evaluated in zebrafish larvae. Results:The Polo-like kinase 4 (PLK4) was identified as the kinase that resulted in higher impairment of cell proliferation when mutated by CRISPR/Cas9. PLK4 CRISPR-mutated rhabdoid cells demonstrated significant decrease in proliferation, viability, and survival. GE showed upregulation of PLK4 in rhabdoid tumors and other embryonal tumors of the brain. The PLK4 inhibitor CFI-400945 showed cytotoxic effects on rhabdoid tumor cell lines while sparing non-neoplastic human fibroblasts and developing zebrafish larvae. Conclusions:Our findings indicate that rhabdoid tumor cell proliferation is highly dependent on PLK4 and suggest that targeting PLK4 with small-molecule inhibitors may hold a novel strategy for the treatment of MRT and possibly other embryonal tumors of the brain. This is the first time that PLK4 has been described as a potential target for both brain and pediatric tumors.

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Section: Plk4 Is Overexpressed In Mrts Rtk At/rts and Other Embryomentioning

confidence: 74%

Section: Resultsmentioning

confidence: 99%

“…A total of 116 samples were included in the study (Supplementary Table S4). GE profiling was performed using Illumina HT‐12v.4 BeadChip whole‐genome expression arrays (Illumina, USA) …”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

A functional screening of the kinome identifies the Polo‐like kinase 4 as a potential therapeutic target for malignant rhabdoid tumors, and possibly, other embryonal tumors of the brain

Sredni

Suzuki

Yang

et al. 2017

Pediatric Blood & Cancer

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“…13 Furthermore, XAB2 may play a role in tumorigenesis. XAB2 expression is significantly downregulated in primary gastric cancer, 14 triple-negative breast cancer 15 and a long-term survivor of an atypical teratoid/rhabdoid tumour, 16 while it is upregulated in ovarian cancer 17 and sarcoma 18 using Oncomine database (www.oncomine.org). The XAB2 tagSNPs (rs794078 and rs4134816) are dramatically correlated with the risk of non-small cell lung cancer in Chinese population.…”

mentioning

confidence: 99%

XAB2 functions in mitotic cell cycle progression via transcriptional regulation of CENPE

Hou

Zhang

et al. 2016

Cell Death Dis

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Xeroderma pigmentosum group A (XPA)-binding protein 2 (XAB2) is a multi-functional protein that plays critical role in processes including transcription, transcription-coupled DNA repair, pre-mRNA splicing, homologous recombination and mRNA export. Microarray analysis on gene expression in XAB2 knockdown cells reveals that many genes with significant change in expression function in mitotic cell cycle regulation. Fluorescence-activated cell scanner analysis confirmed XAB2 depletion led to cell arrest in G2/M phase, mostly at prophase or prometaphase. Live cell imaging further disclosed that XAB2 knockdown induced severe mitotic defects including chromosome misalignment and defects in segregation, leading to mitotic arrest, mitotic catastrophe and subsequent cell death. Among top genes down-regulated by XAB2 depletion is mitotic motor protein centrosome-associated protein E (CENPE). Knockdown CENPE showed similar phenotypes to loss of XAB2, but CENPE knockdown followed by XAB2 depletion did not further enhance cell cycle arrest. Luciferase assay on CENPE promoter showed that overexpression of XAB2 increased luciferase activity, whereas XAB2 depletion resulted in striking reduction of luciferase activity. Further mapping revealed a region in CENPE promoter that is required for the transcriptional regulation by XAB2. Moreover, ChIP assay showed that XAB2 interacted with CENPE promoter. Together, these results support a novel function of XAB2 in mitotic cell cycle regulation, which is partially mediated by transcription regulation on CENPE.

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A gene signature for a long-term survivor of an atypical teratoid/rhabdoid tumor

Cited by 2 publications

References 23 publications

A functional screening of the kinome identifies the Polo‐like kinase 4 as a potential therapeutic target for malignant rhabdoid tumors, and possibly, other embryonal tumors of the brain

A functional screening of the kinome identifies the Polo‐like kinase 4 as a potential therapeutic target for malignant rhabdoid tumors, and possibly, other embryonal tumors of the brain

XAB2 functions in mitotic cell cycle progression via transcriptional regulation of CENPE

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