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EZH2 upregulates the PI3K/AKT pathway through IGF1R and MYC in clinically aggressive chronic lymphocytic leukaemia

Artikel i vetenskaplig tidskrift
Författare Subazini Thankaswamy Kosalai
M. H. A. Morsy
N. Papakonstantinou
L. Mansouri
N. Stavroyianni
Chandrasekhar Kanduri
K. Stamatopoulos
R. Rosenquist
M. Kanduri
Publicerad i Epigenetics
Volym 14
Nummer/häfte 11
Sidor 1125-1140
ISSN 1559-2294
Publiceringsår 2019
Publicerad vid Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi
Sidor 1125-1140
Språk en
Länkar dx.doi.org/10.1080/15592294.2019.16...
Ämnesord Chronic lymphocytic leukemia, EZH2, ChIP sequencing, PI3K pathway, IGFR1, group protein ezh2, breast-cancer, overexpression, lymphoma, target, expression, proliferation, methylation, inhibition, idelalisib, Biochemistry & Molecular Biology, Genetics & Heredity
Ämneskategorier Biokemi och molekylärbiologi

Sammanfattning

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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Denna text är utskriven från följande webbsida:
http://www.gu.se/forskning/publikation/?publicationId=282249
Utskriftsdatum: 2019-10-23