<i>Cic</i> Loss Promotes Gliomagenesis via Aberrant Neural Stem Cell Proliferation and Differentiation

Yang, Rui; Chen, Lee H.; Hansen, Landon J.; Carpenter, Austin B.; Moure, Casey J.; Liu, Heng; Pirozzi, Christopher J.; Diplas, Bill H.; Waitkus, Matthew S.; Greer, Paula K.; Zhu, Huishan; McLendon, Roger E.; Bigner, Darell D.; He, Yiping; Yan, Hai

doi:10.1158/0008-5472.can-17-1018

Cited by 48 publications

(57 citation statements)

References 56 publications

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“…There are some notable differences between the work reported by Yang, et al (13), however, and our present studies. One difference is that the prior study used HOG cells that, despite their historic name, do not carry the ODG-defining genetic features of 1p19q loss or CIC mutation;; similarly the Pdgfraamplified/overexpressed mouse glioma model used is more akin to an RTK-driven GBM than it is to ODG.…”

Section: Discussioncontrasting

confidence: 99%

“…With respect to neural stem cell proliferation, glial fates, and the implications for ODG;; our findings build on the recent discovery that CIC deficiency increases proliferation and self-renewal of NSCs and results in an increased population of OPCs in the brain (13). In reporting these findings, our work also provides a foundation for understanding the relationship between CIC loss and ODG biology -as both dysregulated proliferation and the persistence of an immature OPC phenotype are cardinal features of this cancer.…”

Section: Discussionmentioning

confidence: 59%

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Capicua regulates neural stem cell proliferation and lineage specification through control of Ets factors

Ahmad

Rogers

Chen

et al. 2018

Preprint

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23 3330 Hospital Drive NW 24 Calgary, AB T2N 4N1 25 Canada 26 jawchan@ucalgary.ca 27 28 ABSTRACT 32Capicua (Cic) is a transcriptional repressor mutated in the brain cancer 33 oligodendroglioma. Despite its cancer link, little is known of Cic's function in the 34 brain. Here, we investigated the relationship between Cic expression and cell type 35 specification in the brain. Cic is strongly expressed in astrocytic and neuronal 36 lineage cells but is more weakly expressed in stem cells and oligodendroglial lineage 37 cells. Using a new conditional Cic knockout mouse, we show that forebrain-specific 38 Cic deletion increases proliferation and self-renewal of neural stem cells. 39 Furthermore, Cic loss biases neural stem cells toward glial lineage selection, 40 expanding the pool of oligodendrocyte precursor cells (OPCs). These proliferation 41 and lineage selection effects in the developing brain are dependent on de-repression 42 of Ets transcription factors. In patient-derived oligodendroglioma cells, CIC re-43 expression or ETV5 blockade decreases lineage bias, proliferation, self-renewal and 44 tumorigenicity. Our results identify Cic is an important regulator of cell fate in 45 neurodevelopment and oligodendroglioma, and suggest that its loss contributes to 46 oligodendroglioma by promoting proliferation and an OPC-like identity via Ets 47 overactivity. 48 49 INTRODUCTION 50 51The identification of genes recurrently mutated in cancer often presents opportunities to uncover 52 previously unappreciated mechanisms regulating normal development, and vice versa. The 53 transcriptional repressor Capicua (CIC) has been identified as a likely tumour suppressor gene, as 54 recurrent mutations in CIC and/or reduced expression of CIC are found in several cancer types. In the 55 brain, CIC mutations are nearly exclusively found in oligodendrogliomas (ODGs) -glial tumors that 56 are composed of cells resembling oligodendrocyte precursor cells (1, 2). Indeed, concurrent IDH1/2 57 mutation, single-copy whole-arm losses of 1p and 19q, and mutation of the remaining copy of CIC on 58 chr 19q13 are highly characteristic of ODG and are not found in other cancer types (3-5). These 59 associations suggest a unique relationship between CIC and glial biology. 61Prior work in Drosophila and in mammalian cultured cells has shown that Cic is a transcriptional 62 repressor downstream of receptor tyrosine kinase (RTK) signalling (6). Binding of Cic to the sequence 63 T(G/C)AATG(G/A)A in enhancers and promoters leads to transcriptional repression of its target genes 64 (7, 8). This default repression is relieved upon RTK signalling (6,(9)(10)(11), permitting transcription of 65 targets -among which are PEA3/ETS transcription factors ETV1/4/5 (12). To date, there is limited 66 knowledge of Cic's function in mammalian development or in the brain. Recently, Yang et al. using Cic 67 conditional knockout mice, reported that Cic loss increases a population of proliferating Olig2+ cells in 68 the brain, and that ) loss of Cic potentiates glial tum...

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 59%

Capicua regulates neural stem cell proliferation and lineage specification through control of Ets factors

Ahmad

Rogers

Chen

et al. 2018

Preprint

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“…The fact that many of these genes are also down-regulated in response to KRAS activation, and that CIC is a downstream effector of KRAS, suggests that CIC might act downstream of KRAS as a transcriptional activator. A similar hypothesis has been recently proposed by others (21). In two of the six Cic-null tumors, we identified truncating mutations located in the PEST domain of NOTCH1.…”

Section: Discussionsupporting

confidence: 88%

“…CIC loss of heterozygosity (LOH) frequently occurs in oligodendroglioma with 1p19q codeletion (19,20). While neuron/ glia-specific Cic knockout mice fail to develop brain tumors (5,14), loss of Cic promotes tumor development in a PDGFB-driven orthotopic mouse model of glioma (21). These data hint that loss of CIC alone is not sufficient to drive gliomagenesis.…”

Section: Significancementioning

confidence: 99%

Loss of Capicua alters early T cell development and predisposes mice to T cell lymphoblastic leukemia/lymphoma

Tan

Brunetti

Rousseaux

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Capicua (CIC) regulates a transcriptional network downstream of the RAS/MAPK signaling cascade. In , CIC is important for many developmental processes, including embryonic patterning and specification of wing veins. In humans, CIC has been implicated in neurological diseases, including spinocerebellar ataxia type 1 (SCA1) and a neurodevelopmental syndrome. Additionally, we and others have reported mutations in in several cancers. However, whether CIC is a tumor suppressor remains to be formally tested. In this study, we found that deletion of in adult mice causes T cell acute lymphoblastic leukemia/lymphoma (T-ALL). Using hematopoietic-specific deletion and bone marrow transplantation studies, we show that loss of from hematopoietic cells is sufficient to drive T-ALL. -null tumors show up-regulation of the KRAS pathway as well as activation of the NOTCH1 and MYC transcriptional programs. In sum, we demonstrate that loss of CIC causes T-ALL, establishing it as a tumor suppressor for lymphoid malignancies. Moreover, we show that mouse models lacking CIC in the hematopoietic system are robust models for studying the role of RAS signaling as well as NOTCH1 and MYC transcriptional programs in T-ALL.

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“…CIC-DUX4 fusion proteins activate the expression of ETV1, ETV4, and ETV5, which encode oncogenic transcription factors 18 , thereby promoting cancer progression 17 . Many studies have verified that CIC functions as a tumor suppressor in various types of cancer [19][20][21][22][23][24][25][26][27][28] . Endogenous functions of CIC have been elucidated by examinations of the phenotypes of Cic mutant mice.…”

Section: Introductionmentioning

confidence: 99%

Regulation and function of capicua in mammals

Lee

2020

Exp Mol Med

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Capicua (CIC) is an evolutionarily conserved transcription factor. CIC contains a high-mobility group (HMG) box that recognizes specific DNA sequences to regulate the expression of various target genes. CIC was originally identified in Drosophila melanogaster as a transcriptional repressor that suppresses the receptor tyrosine kinase signaling pathway. This molecule controls normal organ growth and tissue patterning as well as embryogenesis in Drosophila. Recent studies have also demonstrated its extensive functions in mammals. For example, CIC regulates several developmental and physiological processes, including lung development, abdominal wall closure during embryogenesis, brain development and function, neural stem cell homeostasis, T cell differentiation, and enterohepatic circulation of bile acids. CIC is also associated with the progression of various types of cancer and neurodegeneration in spinocerebellar ataxia type-1, systemic autoimmunity, and liver injury. In this review, I provide a broad overview of our current understanding of the regulation and functions of CIC in mammals and discuss future research directions.

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Cic Loss Promotes Gliomagenesis via Aberrant Neural Stem Cell Proliferation and Differentiation

Cited by 48 publications

References 56 publications

Capicua regulates neural stem cell proliferation and lineage specification through control of Ets factors

Capicua regulates neural stem cell proliferation and lineage specification through control of Ets factors

Loss of Capicua alters early T cell development and predisposes mice to T cell lymphoblastic leukemia/lymphoma

Regulation and function of capicua in mammals

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