TCF4 (E2-2) harbors tumor suppressive functions in SHH medulloblastoma

Hellwig, Malte; Lauffer, Marlen C.; Bockmayr, Michael; Spohn, Michael; Merk, Daniel J.; Harrison, Luke; Ahlfeld, Julia; Kitowski, Annabel; Neumann, Julia; Ohli, Jasmin; Holdhof, Dörthe; Niesen, Judith; Schoof, Melanie; Kool, Marcel; Kraus, Cornelia; Zweier, Christiane; Holmberg, Dan; Schüller, Ulrich

doi:10.1007/s00401-019-01982-5

Cited by 23 publications

(23 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TCF4 (also known as ITF2) is a basic helix-loop-helix (bHLH) TF that plays a crucial role in the differentiation and specification of central nervous system (CNS) ( 45 , 50 ). Interestingly, depending on different tumor types, TCF4 functions as either an oncogene (diffuse large B-cell lymphoma) ( 51 ) or tumor suppressor (medulloblastoma and colon cancer) ( 52 , 53 ). KLF15 is a key regulator of metabolic pathways controlling adipogenesis and gluconeogenesis in both liver and skeletal muscles ( 54 , 55 ).…”

Section: Discussionmentioning

confidence: 99%

EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma

Shi

Zheng

Jiang

et al. 2020

Nucleic Acids Research

View full text Add to dashboard Cite

Core regulatory circuitry (CRC)-dependent transcriptional network is critical for developmental tumors in children and adolescents carrying few gene mutations. However, whether and how CRC contributes to transcription regulation in Ewing sarcoma is unknown. Here, we identify and functionally validate a CRC ‘trio’ constituted by three transcription factors (TFs): KLF15, TCF4 and NKX2-2, in Ewing sarcoma cells. Epigenomic analyses demonstrate that EWS-FLI1, the primary fusion driver for this cancer, directly establishes super-enhancers of each of these three TFs to activate their transcription. In turn, KLF15, TCF4 and NKX2-2 co-bind to their own and each other's super-enhancers and promoters, forming an inter-connected auto-regulatory loop. Functionally, CRC factors contribute significantly to cell proliferation of Ewing sarcoma both in vitro and in vivo. Mechanistically, CRC factors exhibit prominent capacity of co-regulating the epigenome in cooperation with EWS-FLI1, occupying 77.2% of promoters and 55.6% of enhancers genome-wide. Downstream, CRC TFs coordinately regulate gene expression networks in Ewing sarcoma, controlling important signaling pathways for cancer, such as lipid metabolism pathway, PI3K/AKT and MAPK signaling pathways. Together, molecular characterization of the oncogenic CRC model advances our understanding of the biology of Ewing sarcoma. Moreover, CRC-downstream genes and signaling pathways may contain potential therapeutic targets for this malignancy.

show abstract

Section: Discussionmentioning

confidence: 99%

EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma

Shi

Zheng

Jiang

et al. 2020

Nucleic Acids Research

View full text Add to dashboard Cite

show abstract

“…More recently, studies have also proposed targeting of the PD-1/PD-L1 axis for immune checkpoint suppression as a therapy for different tumors including HNSCC [12]. The transcription factor 4 (TCF-4) (also ITF2, SEF2 or E2–2) is a commonly widely considered to be a broadly expressed basic helix–loop–helix (bHLH) protein that serves as a homo- or heterodimer [13], with reports highlighting the tumor-suppressive capabilities of TCF-4 in tumors such as the Sonic hedgehog (SHH) medulloblastoma [13, 14]. Moreover, another study identified the presence of a target relationship between let-7 and transcription factor, with evidence suggesting that let-7 targets the lineage-specific transcription factor PLZF in regulating effector function and cell differentiation [15].…”

Section: Introductionmentioning

confidence: 99%

The let-7 family of microRNAs suppresses immune evasion in head and neck squamous cell carcinoma by promoting PD-L1 degradation

Liu

Han

et al. 2019

Cell Commun Signal

View full text Add to dashboard Cite

Background: Accumulation of immunosuppressive protein programmed death-ligand 1 (PD-L1) has been documented in several cancers and contributes to the evasion of the host immune system. However, cancer cellintrinsic signaling-dependent control of PD-L1 expression remains to be elucidated. Herein, we aimed to identify the let-7 family of microRNAs as candidates that up-regulate tumor cell PD-L1 expression and mediates immune evasion of head and neck squamous cell carcinoma (HNSCC). Methods: The expression of let-7 family and PD-L1 was quantified in HNSCC tissues and adjacent normal tissues. PD-L1 degradation was evaluated in HNSCC cells in response to elevated expressions of let-7a or let-7b. The regulation of let-7 family on PD-L1 degradation through a mechanism involving T-cell factor-4 (TCF-4) control of βcatenin/STT3 pathway was evaluated. Immune recognition of HNSCC in vivo was examined in subcutaneous tumorbearing C3H mice in the presence of let-7a/b and/or CTLA-4 antibody. Results: The let-7 family were significantly down-regulated in the context of HNSCC, sharing a negative correlation with PD-L1 expression. Glycosylated PD-L1 was detected in HNSCC cells, which was reduced by let-7a/b overexpression. TCF-4, the target of let-7a/b, activated the β-catenin/STT3 pathway and promoted PD-L1 degradation. In vivo analysis demonstrated that let-7a/b over-expression potentiated anticancer immunotherapy by CTLA-4 blockade. Conclusions: Taken together, our findings highlight targeting let-7 family as a potential strategy to enhance immune checkpoint therapy for HNSCC.

show abstract

“…Matching our data, differences in the expression of genes associated with axon/neuronal development (Xia et al, ), axon guidance (Doostparast Torshizi et al, ), neuronal differentiation (Quevedo et al, ) and growth (Doostparast Torshizi et al, ) have been described following TCF4 knockdown in vitro. Other studies have reported that TCF4 knockdown in vitro rather leads to a differential expression of genes mainly involved in cell cycle regulation and apoptosis (Hill et al, ; Moen et al, ), especially in the context of the putative tumour‐suppressive role of TCF4 in cancer development (Hellwig et al, ; Herbst, Helferich, Behrens, Goke, & Kolligs, ). This might seem incompatible with the other studies.…”

Section: Discussionmentioning

confidence: 99%

“…PTHS was first described in 1978 (Pitt & Hopkins, ) and in 2007, germline mutations in the gene encoding TCF4 were identified as the cause of the syndrome (Amiel et al, ; Brockschmidt et al, ; Zweier et al, ). Besides, a tumour‐suppressive role of TCF4 in medulloblastoma was described, highlighting the importance of the transcription factor (TF) in developmental processes (Hellwig et al, ).…”

Section: Introductionmentioning

confidence: 99%

The basic helix‐loop‐helix transcription factor TCF4 impacts brain architecture as well as neuronal morphology and differentiation

Schoof

Hellwig

Harrison

et al. 2020

Eur J of Neuroscience

Self Cite

View full text Add to dashboard Cite

Germline mutations in the basic helix‐loop‐helix transcription factor 4 (TCF4) cause the Pitt–Hopkins syndrome (PTHS), a developmental disorder with severe intellectual disability. Here, we report findings from a new mouse model with a central nervous system‐specific truncation of Tcf4 leading to severe phenotypic abnormalities. Furthermore, it allows the study of a complete TCF4 knockout in adult mice, circumventing early postnatal lethality of previously published mouse models. Our data suggest that a TCF4 truncation results in an impaired hippocampal architecture affecting both the dentate gyrus as well as the cornu ammonis. In the cerebral cortex, loss of TCF4 generates a severe differentiation delay of neural precursors. Furthermore, neuronal morphology was critically affected with shortened apical dendrites and significantly increased branching of dendrites. Our data provide novel information about the role of Tcf4 in brain development and may help to understand the mechanisms leading to intellectual deficits observed in patients suffering from PTHS.

show abstract

TCF4 (E2-2) harbors tumor suppressive functions in SHH medulloblastoma

Cited by 23 publications

References 79 publications

EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma

EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma

The let-7 family of microRNAs suppresses immune evasion in head and neck squamous cell carcinoma by promoting PD-L1 degradation

The basic helix‐loop‐helix transcription factor TCF4 impacts brain architecture as well as neuronal morphology and differentiation

Contact Info

Product

Resources

About