NELL2-cdc42 signaling regulates BAF complexes and Ewing sarcoma cell growth

Jayabal, Panneerselvam; Zhou, Fuchun; Lei, Xiufen; Ma, Xiuye; Blackman, Barron; Weintraub, Susan T.; Houghton, Peter J.; Shiio, Yuzuru

doi:10.1016/j.celrep.2021.109254

Cited by 12 publications

(51 citation statements)

References 61 publications

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“…We recently reported that the silencing of NELL2 in Ewing sarcoma cells profoundly impairs anchorage-dependent and anchorage-independent growth and xenograft tumorigenicity [ 5 ]. Upon further investigation, we discovered that NELL2 silencing by siRNA transfection or lentiviral shRNA expression results in the induction of interferon β1, interferon-stimulated genes (Mx1 and OAS1), and a cyclin-dependent kinase inhibitor p21 (CDKN1A) in Ewing sarcoma cells ( Figure 1A – 1F ), which was suppressed by the addition of recombinant NELL2 protein to the culture medium ( Figure 1G ).…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…We recently reported that Ewing sarcoma depends on the autocrine signaling mediated by a cytokine, NELL2 [ 5 ]. NELL2 binds to a receptor, Robo3, and stimulates the EWS-FLI1 transcriptional output through inactivation of cdc42, which disassembles and destabilizes the BAF complexes [ 5 ]. We identified two populations of cells in Ewing sarcoma, NELL2 high CD133 high EWS-FLI1 high and NELL2 low CD133 low EWS-FLI1 low , which display phenotypes consistent with high and low NELL2 signaling, respectively [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…NELL2 binds to a receptor, Robo3, and stimulates the EWS-FLI1 transcriptional output through inactivation of cdc42, which disassembles and destabilizes the BAF complexes [ 5 ]. We identified two populations of cells in Ewing sarcoma, NELL2 high CD133 high EWS-FLI1 high and NELL2 low CD133 low EWS-FLI1 low , which display phenotypes consistent with high and low NELL2 signaling, respectively [ 5 ]. NELL2, CD133, and EWS-FLI1 positively regulate each other and upregulate the BAF complexes and cell proliferation in Ewing sarcoma [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…We identified two populations of cells in Ewing sarcoma, NELL2 high CD133 high EWS-FLI1 high and NELL2 low CD133 low EWS-FLI1 low , which display phenotypes consistent with high and low NELL2 signaling, respectively [ 5 ]. NELL2, CD133, and EWS-FLI1 positively regulate each other and upregulate the BAF complexes and cell proliferation in Ewing sarcoma [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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EZH2 suppresses endogenous retroviruses and an interferon response in cancers

Jayabal

Shiio

2021

Genes Cancer

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Ewing sarcoma is an aggressive cancer of bone and soft tissue in children. It is characterized by the chromosomal translocation between EWS and an Ets family transcription factor, most commonly FLI1. We recently reported that Ewing sarcoma depends on the autocrine signaling mediated by a cytokine, NELL2. NELL2 signaling stimulates the transcriptional output of EWS-FLI1 through the BAF chromatin remodeling complexes. While studying the impact of NELL2 silencing on Ewing sarcoma, we found that suppression of NELL2 signaling induces the expression of endogenous retroviruses (ERVs) and LINE-1 retrotransposons, an interferon response, and growth arrest. We determined that a histone methyltransferase, EZH2, is the critical downstream target of NELL2 signaling in suppressing ERVs, LINE-1, an interferon response, and growth arrest. We show that EZH2 inhibitors induce ERVs, LINE-1, and an interferon response in a variety of cancer types. These results uncover the role for NELL2–EZH2 signaling in suppressing endogenous virus-like agents and an antiviral response, and suggest the potential utility of EZH2 inhibitors in enhancing anti-tumor immunity.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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EZH2 suppresses endogenous retroviruses and an interferon response in cancers

Jayabal

Shiio

2021

Genes Cancer

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Functional Roles of CD133: More than Stemness Associated Factor Regulated by the Microenvironment

Moreno-Londoño,

Robles-Flores

2023

Stem Cell Rev and Rep

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CD133 protein has been one of the most used surface markers to select and identify cancer cells with stem-like features. However, its expression is not restricted to tumoral cells; it is also expressed in differentiated cells and stem/progenitor cells in various normal tissues. CD133 participates in several cellular processes, in part orchestrating signal transduction of essential pathways that frequently are dysregulated in cancer, such as PI3K/Akt signaling and the Wnt/β-catenin pathway. CD133 expression correlates with enhanced cell self-renewal, migration, invasion, and survival under stress conditions in cancer. Aside from the intrinsic cell mechanisms that regulate CD133 expression in each cellular type, extrinsic factors from the surrounding niche can also impact CD33 levels. The enhanced CD133 expression in cells can confer adaptive advantages by amplifying the activation of a specific signaling pathway in a context-dependent manner. In this review, we do not only describe the CD133 physiological functions known so far, but importantly, we analyze how the microenvironment changes impact the regulation of CD133 functions emphasizing its value as a marker of cell adaptability beyond a cancer-stem cell marker. Graphical Abstract

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NELL2-cdc42 signaling regulates BAF complexes and Ewing sarcoma cell growth

Cited by 12 publications

References 61 publications

EZH2 suppresses endogenous retroviruses and an interferon response in cancers

EZH2 suppresses endogenous retroviruses and an interferon response in cancers

Functional Roles of CD133: More than Stemness Associated Factor Regulated by the Microenvironment

Nitric oxide suppression by secreted frizzled-related protein 2 drives retinoblastoma

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