Functional relevance of genes predicted to be affected by epigenetic alterations in atypical teratoid/rhabdoid tumors

被引：8

作者：

Tegeder, Isabel ^{[1
]}

Thiel, Katharina ^{[1
]}

Erkek, Serap ^{[2
,3
,4
]}

Johann, Pascal D. ^{[2
,3
,4
,5
]}

Berlandi, Johannes ^{[1
]}

Thatikonda, Venu ^{[2
,3
,4
]}

Fruehwald, Michael C. ^{[6
]}

Kool, Marcel ^{[2
,3
,4
]}

Jeibmann, Astrid ^{[1
]}

Hasselblatt, Martin ^{[1
]}

机构：

[1] Univ Hosp Munster, Inst Neuropathol, Pottkamp 2, D-48149 Munster, Germany

[2] NCT Heidelberg, Hopp Childrens Canc Ctr, Neuenheimer Feld 280, D-69120 Heidelberg, Germany

[3] German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany

[4] German Canc Consortium DKTK, D-69120 Heidelberg, Germany

[5] Univ Hosp Heidelberg, Dept Pediat Oncol & Hematol, Neuenheimer Feld 430, D-69120 Heidelberg, Germany

[6] Childrens Hosp Augsburg, Swabian Childrens Canc Ctr, Stenglinstr 2, D-86156 Augsburg, Germany

来源：

JOURNAL OF NEURO-ONCOLOGY | 2019年 / 141卷 / 01期

关键词：

Drosophila melanogaster; Malignant rhabdoid tumor; Histone modifications; SMARCB1; TGFbeta signaling; PRDM16; EXPRESSION; MUTATIONS; PATHWAY; BIOLOGY; BROWN; FAT; SUBGROUPS; PROFILES; IDENTIFY; ABSENCE;

D O I：

10.1007/s11060-018-03018-6

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly arising in infants. Mutations of SWI/SNF chromatin remodeling complex members SMARCB1/INI1 or (rarely) SMARCA4/Brg1 are the sole recurrent genetic lesions. Epigenetic studies revealed a large number of genes predicted to be affected by differential histone modifications in ATRT, but the role of these genes in the biology of ATRT remains uncertain. We therefore aimed at exploring the role of these genes in the detrimental effects of SMARCB1-deficiency. Methods The functional relevance of 1083 genes predicted to be affected by epigenetic alterations in ATRT was examined in vivo using a Drosophila melanogaster model of SMARCB1-deficiency. Human orthologues of genes whose knockdown modified the phenotype in the Gal4-UAS fly model were further examined in ATRT samples and SMARCB1-deficient rhabdoid tumor cells. Results Knockdown of Snr1, the fly orthologue of SMARCB1, resulted in a lethal phenotype and epigenetic alterations in the fly model. The lethal phenotype was shifted to later stages of development upon additional siRNA knockdown of 89 of 1083 genes screened in vivo. These included TGF-beta receptor signaling pathway related genes, e.g. CG10348, the fly orthologue of transcriptional regulator PRDM16. Subsequently, PRDM16 was found to be over-expressed in ATRT samples and knockdown of PRDM16 in SMARCB1-deficient rhabdoid tumor cells reduced proliferation. Conclusions These results suggest that a subset of genes affected by differential histone modification in ATRT is involved in the detrimental effects of SMARCB1-deficiency and also relevant in the biology of ATRT.

引用

页码：43 / 55

页数：13