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EZH2 upregulates th...
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Kosalai, Subazini Thankaswamy,1980Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
(författare)
EZH2 upregulates the PI3K/AKT pathway through IGF1R and MYC in clinically aggressive chronic lymphocytic leukaemia
- Artikel/kapitelEngelska2019
Förlag, utgivningsår, omfång ...
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2019-06-26
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Informa UK Limited,2019
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LIBRIS-ID:oai:gup.ub.gu.se/282249
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https://gup.ub.gu.se/publication/282249URI
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https://doi.org/10.1080/15592294.2019.1633867DOI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:141277583URI
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EZH2 is overexpressed in poor-prognostic chronic lymphocytic leukaemia (CLL) cases, acting as an oncogene; however, thus far, the EZH2 target genes in CLL have not been disclosed. In this study, using ChIP-sequencing, we identified EZH2 and H3K27me3 target genes in two prognostic subgroups of CLL with distinct prognosis and outcome, i.e., cases with unmutated (U-CLL, n = 6) or mutated IGHV genes (M-CLL, n = 6). While the majority of oncogenic pathways were equally enriched for EZH2 target genes in both prognostic subgroups, PI3K pathway genes were differentially bound by EZH2 in U-CLL versus M-CLL. The occupancy of EZH2 for selected PI3K pathway target genes was validated in additional CLL samples (n = 16) and CLL cell lines using siRNA-mediated EZH2 downregulation and ChIP assays. Intriguingly, we found that EZH2 directly binds to the IGF1R promoter along with MYC and upregulates IGF1R expression in U-CLL, leading to downstream PI3K activation. By investigating an independent CLL cohort (n = 96), a positive correlation was observed between EZH2 and IGF1R expression with higher levels in U-CLL compared to M-CLL. Accordingly, siRNA-mediated downregulation of either EZH2, MYC or IGF1R and treatment with EZH2 and MYC pharmacological inhibitors in the HG3 CLL cell line induced a significant reduction in PI3K pathway activation. In conclusion, we characterize for the first time EZH2 target genes in CLL revealing a hitherto unknown implication of EZH2 in modulating the PI3K pathway in a non-canonical, PRC2-independent way, with potential therapeutic implications considering that PI3K inhibitors are effective therapeutic agents for CLL.
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Biuppslag (personer, institutioner, konferenser, titlar ...)
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Morsy, Mohammad Hamdy Abdelrazak,1986
(författare)
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Papakonstantinou, N.
(författare)
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Mansouri, L.Karolinska Institutet
(författare)
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Stavroyianni, N.
(författare)
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Kanduri, Chandrasekhar,1967Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology(Swepub:gu)xchaka
(författare)
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Stamatopoulos, K.
(författare)
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Rosenquist, R.Karolinska Institutet
(författare)
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Kanduri, Meena,1974
(författare)
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Göteborgs universitetInstitutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Epigenetics: Informa UK Limited14:11, s. 1125-11401559-22941559-2308
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