Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma

被引：96

作者：

Michealraj, Kulandaimanuvel Antony ^{[1
,2
]}

Kumar, Sachin A. ^{[2
,3
]}

Kim, Leo J. Y. ^{[4
]}

Cavalli, Florence M. G. ^{[1
,2
]}

Przelicki, David ^{[1
,2
,3
]}

Wojcik, John B. ^{[5
,6
]}

Delaidelli, Alberto ^{[7
,8
]}

Bajic, Andrea ^{[9
]}

Saulnier, Olivier ^{[1
,2
]}

MacLeod, Graham ^{[10
]}

Vellanki, Ravi N. ^{[13
]}

Vladoiu, Maria C. ^{[1
,2
,3
]}

Guilhamon, Paul ^{[1
,2
]}

Ong, Winnie ^{[2
,3
]}

Lee, John J. Y. ^{[1
,2
,3
]}

Jiang, Yanqing ^{[2
]}

Holgado, Borja L. ^{[1
,2
]}

Rasnitsyn, Alex ^{[1
,2
,11
]}

Malik, Ahmad A. ^{[12
,18
]}

Tsai, Ricky ^{[12
]}

Richman, Cory M. ^{[1
,2
,11
]}

Juraschka, Kyle ^{[1
,2
,3
]}

Haapasalo, Joonas ^{[1
,2
]}

Wang, Evan Y. ^{[1
,2
,11
]}

De Antonellis, Pasqualino ^{[1
,2
]}

Suzuki, Hiromichi ^{[1
,2
]}

Farooq, Hamza ^{[1
,2
]}

Balin, Polina ^{[1
,2
,3
]}

Kharas, Kaitlin ^{[1
,2
,3
]}

Van Ommeren, Randy ^{[2
,3
]}

Sirbu, Olga ^{[1
,2
,11
]}

Rastan, Avesta ^{[1
,2
]}

Krumholtz, Stacey L. ^{[2
]}

Ly, Michelle ^{[1
,2
,3
]}

Ahmadi, Moloud ^{[10
]}

Deblois, Genevieve ^{[13
]}

Srikanthan, Dilakshan ^{[1
,2
,3
]}

Luu, Betty ^{[1
,2
]}

Loukides, James ^{[1
,2
]}

Wu, Xiaochong ^{[2
]}

Garzia, Livia ^{[14
]}

Ramaswamy, Vijay ^{[15
]}

Kanshin, Evgeny ^{[16
]}

Sanchez-Osuna, Maria ^{[16
]}

El-Hamamy, Ibrahim ^{[17
,18
]}

Coutinho, Fiona J. ^{[1
,2
]}

Prinos, Panagiotis ^{[19
]}

Singh, Sheila ^{[20
,21
,22
]}

Donovan, Laura K. ^{[1
,2
]}

Daniels, Craig ^{[1
,2
]}

机构：

[1] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON M5G 0A4, Canada

[2] Hosp Sick Children, Dev & Stem Cell Biol Program, Toronto, ON M5G 0A4, Canada

[3] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5G 1L7, Canada

[4] Univ Calif San Diego, Dept Med, Div Regenerat Med, La Jolla, CA 92037 USA

[5] Univ Penn, Perelman Sch Med, Dept Biochem & Biophys, Philadelphia, PA 19104 USA

[6] Univ Penn, Perelman Sch Med, Penn Epigenet Inst, Philadelphia, PA 19104 USA

[7] British Columbia Canc Res Ctr, Dept Mol Oncol, Vancouver, BC V6T 1Z2, Canada

[8] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V6T 1Z2, Canada

[9] McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada

[10] Univ Toronto, Leslie Dan Fac Pharm, Toronto, ON M5S 3M2, Canada

[11] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada

[12] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Ctr Mol & Syst Biol, Toronto, ON, Canada

[13] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 1L7, Canada

[14] McGill Univ, Hlth Ctr, Res Inst, Canc Res Program, Montreal, PQ H4A 3J1, Canada

[15] Hosp Sick Children, Dept Pediat, Div Haematol Oncol, Toronto, ON M5G 1X8, Canada

[16] Univ Montreal, Dept Med, Inst Res Immunol & Canc IRIC, Montreal, PQ H3C 3J7, Canada

[17] Ontario Inst Canc Res, Computat Biol Program, Adapt Oncol Theme, Toronto, ON M5G 0A3, Canada

[18] Univ Toronto, Dept Mol Genet, Toronto, ON M5G 1L7, Canada

[19] Univ Toronto, Struct Genom Consortium, MaRS Ctr, 101 Coll St,South Tower, Toronto, ON M5G 1L7, Canada

[20] McMaster Univ, Stem Cell & Canc Res Inst, Hamilton, ON L8S 4K1, Canada

[21] McMaster Univ, Dept Biochem & Biomed Sci, Hamilton, ON L8S 4K1, Canada

[22] McMaster Univ, Dept Surg, Hamilton, ON L8S 4K1, Canada

[23] Univ Calgary, Hotchkiss Brain Inst, Cumming Sch Med, Dept Cell Biol & Anat, Calgary, AB T2N 4N1, Canada

[24] Univ Toronto, Dept Biochem, Fac Med, Toronto, ON, Canada

[25] McGill Univ, Hlth Ctr, Res Inst, Dept Pediat, Montreal, PQ H4A 3J1, Canada

[26] Hosp Sick Children, Div Neurosurg, Toronto, ON M5G 1L7, Canada

[27] Texas Childrens Hosp, Baylor Coll Med, Dept Pediat, Dan L Duncan Canc Ctr,Canc Ctr, Houston, TX 77030 USA

[28] Univ Pittsburgh, Childrens Hosp Pittsburgh, Sch Med, Dept Neurol Surg, Pittsburgh, PA 15213 USA

来源：

CELL | 2020年 / 181卷 / 06期

基金：

美国国家卫生研究院; 加拿大健康研究院; 巴西圣保罗研究基金会;

关键词：

POSTERIOR-FOSSA EPENDYMOMA; READ ALIGNMENT; COPY NUMBER; CELL; HYPOXIA; CANCER; GENES; MUTATIONS; IDENTIFICATION; LIPOGENESIS;

D O I：

10.1016/j.cell.2020.04.047

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.

引用

页码：1329 / +

页数：41

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