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Article ; Online: Author Correction: Ybx1 fine-tunes PRC2 activities to control embryonic brain development.

Evans, Myron K / Matsui, Yurika / Xu, Beisi / Willis, Catherine / Loome, Jennifer / Milburn, Luis / Fan, Yiping / Pagala, Vishwajeeth / Peng, Jamy C

Nature communications

2023 Volume 14, Issue 1, Page(s) 412

Language	English
Publishing date	2023-01-25
Publishing country	England
Document type	Published Erratum
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-36069-z
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Article ; Online: Ybx1 fine-tunes PRC2 activities to control embryonic brain development.

Evans, Myron K / Matsui, Yurika / Xu, Beisi / Willis, Catherine / Loome, Jennifer / Milburn, Luis / Fan, Yiping / Pagala, Vishwajeeth / Peng, Jamy C

Nature communications

2020 Volume 11, Issue 1, Page(s) 4060

Abstract: Chromatin modifiers affect spatiotemporal gene expression programs that underlie organismal development. The Polycomb repressive complex 2 (PRC2) is a crucial chromatin modifier in executing neurodevelopmental programs. Here, we find that PRC2 interacts ... ...

Abstract	Chromatin modifiers affect spatiotemporal gene expression programs that underlie organismal development. The Polycomb repressive complex 2 (PRC2) is a crucial chromatin modifier in executing neurodevelopmental programs. Here, we find that PRC2 interacts with the nucleic acid-binding protein Ybx1. In the mouse embryo in vivo, Ybx1 is required for forebrain specification and restricting mid-hindbrain growth. In neural progenitor cells (NPCs), Ybx1 controls self-renewal and neuronal differentiation. Mechanistically, Ybx1 highly overlaps PRC2 binding genome-wide, controls PRC2 distribution, and inhibits H3K27me3 levels. These functions are consistent with Ybx1-mediated promotion of genes involved in forebrain specification, cell proliferation, or neuronal differentiation. In Ybx1-knockout NPCs, H3K27me3 reduction by PRC2 enzymatic inhibitor or genetic depletion partially rescues gene expression and NPC functions. Our findings suggest that Ybx1 fine-tunes PRC2 activities to regulate spatiotemporal gene expression in embryonic neural development and uncover a crucial epigenetic mechanism balancing forebrain-hindbrain lineages and self-renewal-differentiation choices in NPCs.
MeSH term(s)	Animals ; Blotting, Western ; Brain/embryology ; Brain/metabolism ; Cell Differentiation/genetics ; Cell Differentiation/physiology ; Cell Proliferation/genetics ; Cell Proliferation/physiology ; Cells, Cultured ; Chromatin Immunoprecipitation ; Drosophila ; Epigenesis, Genetic/genetics ; Flow Cytometry ; Fluorescent Antibody Technique ; Histone-Lysine N-Methyltransferase/genetics ; Histone-Lysine N-Methyltransferase/metabolism ; Immunoprecipitation ; Mice ; Mice, Knockout ; Protein Processing, Post-Translational/genetics ; Protein Processing, Post-Translational/physiology ; Reverse Transcriptase Polymerase Chain Reaction ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Transcription Factors ; YB-1 protein, mouse ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43)
Language	English
Publishing date	2020-08-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-020-17878-y
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Article ; Online: Therapeutic HDAC inhibition in hypermutant diffuse intrinsic pontine glioma.

Neoplasia (New York, N.Y.)

2023 Volume 43, Page(s) 100921

Abstract: Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition syndrome associated with the development of hypermutant pediatric high-grade glioma, and confers a poor prognosis. While therapeutic histone deacetylase (HDAC) inhibition of ... ...

Abstract	Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition syndrome associated with the development of hypermutant pediatric high-grade glioma, and confers a poor prognosis. While therapeutic histone deacetylase (HDAC) inhibition of diffuse intrinsic pontine glioma (DIPG) has been reported; here, we use a clinically relevant biopsy-derived hypermutant DIPG model (PBT-24FH) and a CRISPR-Cas9 induced genetic model to evaluate the efficacy of HDAC inhibition against hypermutant DIPG. We screened PBT-24FH cells for sensitivity to a panel of HDAC inhibitors (HDACis) in vitro, identifying two HDACis associated with low nanomolar IC50s, quisinostat (27 nM) and romidepsin (2 nM). In vivo, quisinostat proved more efficacious, inducing near-complete tumor regression in a PBT-24FH flank model. RNA sequencing revealed significant quisinostat-driven changes in gene expression, including upregulation of neural and pro-inflammatory genes. To validate the observed potency of quisinostat in vivo against additional hypermutant DIPG models, we tested quisinostat in genetically-induced mismatch repair (MMR)-deficient DIPG flank tumors, demonstrating that loss of MMR function increases sensitivity to quisinostat in vivo. Here, we establish the preclinical efficacy of quisinostat against hypermutant DIPG, supporting further investigation of epigenetic targeting of hypermutant pediatric cancers with the potential for clinical translation. These findings support further investigation of HDAC inhibitors against pontine high-grade gliomas, beyond only those with histone mutations, as well as against other hypermutant central nervous system tumors.
MeSH term(s)	Humans ; Child ; Diffuse Intrinsic Pontine Glioma/drug therapy ; Diffuse Intrinsic Pontine Glioma/genetics ; Histone Deacetylase Inhibitors/pharmacology ; Histones ; Hydroxamic Acids ; Glioma/drug therapy ; Glioma/genetics
Chemical Substances	quisinostat ; Histone Deacetylase Inhibitors ; Histones ; Hydroxamic Acids
Language	English
Publishing date	2023-08-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1483840-0
ISSN	1476-5586 ; 1522-8002
ISSN (online)	1476-5586
ISSN	1522-8002
DOI	10.1016/j.neo.2023.100921
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Article ; Online: Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity.

Langdon, Casey G / Gadek, Katherine E / Garcia, Matthew R / Evans, Myron K / Reed, Kristin B / Bush, Madeline / Hanna, Jason A / Drummond, Catherine J / Maguire, Matthew C / Leavey, Patrick J / Finkelstein, David / Jin, Hongjian / Schreiner, Patrick A / Rehg, Jerold E / Hatley, Mark E

Nature communications

2021 Volume 12, Issue 1, Page(s) 5520

Abstract: PTEN promoter hypermethylation is nearly universal and PTEN copy number loss occurs in ~25% of fusion-negative rhabdomyosarcoma (FN-RMS). Here we show Pten deletion in a mouse model of FN-RMS results in less differentiated tumors more closely resembling ... ...

Abstract	PTEN promoter hypermethylation is nearly universal and PTEN copy number loss occurs in ~25% of fusion-negative rhabdomyosarcoma (FN-RMS). Here we show Pten deletion in a mouse model of FN-RMS results in less differentiated tumors more closely resembling human embryonal RMS. PTEN loss activated the PI3K pathway but did not increase mTOR activity. In wild-type tumors, PTEN was expressed in the nucleus suggesting loss of nuclear PTEN functions could account for these phenotypes. Pten deleted tumors had increased expression of transcription factors important in neural and skeletal muscle development including Dbx1 and Pax7. Pax7 deletion completely rescued the effects of Pten loss. Strikingly, these Pten;Pax7 deleted tumors were no longer FN-RMS but displayed smooth muscle differentiation similar to leiomyosarcoma. These data highlight how Pten loss in FN-RMS is connected to a PAX7 lineage-specific transcriptional output that creates a dependency or synthetic essentiality on the transcription factor PAX7 to maintain tumor identity.
MeSH term(s)	Animals ; Breeding ; Cell Differentiation ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Homeodomain Proteins/metabolism ; Humans ; Integrases/metabolism ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mice, Knockout ; Muscle Development ; PAX7 Transcription Factor/metabolism ; PTEN Phosphohydrolase/deficiency ; PTEN Phosphohydrolase/metabolism ; Phosphoproteins/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Rhabdomyosarcoma/genetics ; Rhabdomyosarcoma/metabolism ; Rhabdomyosarcoma/pathology ; Mice
Chemical Substances	Dbx1 protein, mouse ; Homeodomain Proteins ; PAX7 Transcription Factor ; Phosphoproteins ; RNA, Messenger ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Cre recombinase (EC 2.7.7.-) ; Integrases (EC 2.7.7.-) ; PTEN Phosphohydrolase (EC 3.1.3.67)
Language	English
Publishing date	2021-09-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-25829-4
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Article ; Online: Mn porphyrin in combination with ascorbate acts as a pro-oxidant and mediates caspase-independent cancer cell death.

Evans, Myron K / Tovmasyan, Artak / Batinic-Haberle, Ines / Devi, Gayathri R

Free radical biology & medicine

2013 Volume 68, Page(s) 302–314

Abstract: Resistance to therapy-mediated apoptosis in inflammatory breast cancer, an aggressive and distinct subtype of breast cancer, was recently attributed to increased superoxide dismutase (SOD) expression, glutathione (GSH) content, and decreased accumulation ...

Abstract	Resistance to therapy-mediated apoptosis in inflammatory breast cancer, an aggressive and distinct subtype of breast cancer, was recently attributed to increased superoxide dismutase (SOD) expression, glutathione (GSH) content, and decreased accumulation of reactive species. In this study, we demonstrate the unique ability of two Mn(III) N-substituted pyridylporphyrin (MnP)-based SOD mimics (MnTE-2-PyP(5+) and MnTnBuOE-2-PyP(5+)) to catalyze oxidation of ascorbate, leading to the production of excessive levels of peroxide, and in turn cell death. The accumulation of peroxide, as a consequence of MnP+ascorbate treatment, was fully reversed by the administration of exogenous catalase, showing that hydrogen peroxide is essential for cell death. Cell death as a consequence of the action of MnP+ascorbate corresponded to decreases in GSH levels, prosurvival signaling (p-NF-κB, p-ERK1/2), and in expression of X-linked inhibitor of apoptosis protein, the most potent caspase inhibitor. Although markers of classical apoptosis were observed, including PARP cleavage and annexin V staining, administration of a pan-caspase inhibitor, Q-VD-OPh, did not reverse the observed cytotoxicity. MnP+ascorbate-treated cells showed nuclear translocation of apoptosis-inducing factor, suggesting the possibility of a mechanism of caspase-independent cell death. Pharmacological ascorbate has already shown promise in recently completed phase I clinical trials, in which its oxidation and subsequent peroxide formation was catalyzed by endogenous metalloproteins. The catalysis of ascorbate oxidation by an optimized metal-based catalyst (such as MnP) carries a large therapeutic potential as an anticancer agent by itself or in combination with other modalities such as radio- and chemotherapy.
MeSH term(s)	Apoptosis/drug effects ; Ascorbic Acid/metabolism ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Caspases/genetics ; Female ; Humans ; Hydrogen Peroxide/metabolism ; Metalloporphyrins/administration & dosage ; NF-kappa B/metabolism ; Oxidation-Reduction ; Peroxides/metabolism ; Peroxides/toxicity ; Reactive Oxygen Species/metabolism ; Reactive Oxygen Species/toxicity ; Superoxide Dismutase/metabolism
Chemical Substances	Metalloporphyrins ; NF-kappa B ; Peroxides ; Reactive Oxygen Species ; manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin ; Hydrogen Peroxide (BBX060AN9V) ; Superoxide Dismutase (EC 1.15.1.1) ; Caspases (EC 3.4.22.-) ; Ascorbic Acid (PQ6CK8PD0R)
Language	English
Publishing date	2013-12-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	807032-5
ISSN	1873-4596 ; 0891-5849
ISSN (online)	1873-4596
ISSN	0891-5849
DOI	10.1016/j.freeradbiomed.2013.11.031
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Article ; Online: XIAP Regulation by MNK Links MAPK and NFκB Signaling to Determine an Aggressive Breast Cancer Phenotype.

Evans, Myron K / Brown, Michael C / Geradts, Joseph / Bao, Xuhui / Robinson, Timothy J / Jolly, Mohit Kumar / Vermeulen, Peter B / Palmer, Gregory M / Gromeier, Matthias / Levine, Herbert / Morse, Michael A / Van Laere, Steven J / Devi, Gayathri R

Cancer research

2018 Volume 78, Issue 7, Page(s) 1726–1738

Abstract: Hyperactivation of the NFκB pathway is a distinct feature of inflammatory breast cancer (IBC), a highly proliferative and lethal disease. Gene expression studies in IBC patient tissue have linked EGFR (EGFR/HER2)-mediated MAPK signaling to NFκB ... ...

Abstract	Hyperactivation of the NFκB pathway is a distinct feature of inflammatory breast cancer (IBC), a highly proliferative and lethal disease. Gene expression studies in IBC patient tissue have linked EGFR (EGFR/HER2)-mediated MAPK signaling to NFκB hyperactivity, but the mechanism(s) by which this occurs remain unclear. Here, we report that the X-linked inhibitor of apoptosis protein (XIAP) plays a central role in linking these two pathways. XIAP overexpression correlated with poor prognoses in breast cancer patients and was frequently observed in untreated IBC patient primary tumors. XIAP drove constitutive NFκB transcriptional activity, which mediated ALDH positivity (a marker of stem-like cells),
MeSH term(s)	Aldehyde Dehydrogenase/metabolism ; Animals ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cell Movement/drug effects ; ErbB Receptors/metabolism ; Female ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; MAP Kinase Signaling System ; Mice ; Mice, Nude ; Mice, SCID ; NF-kappa B/metabolism ; Protein-Serine-Threonine Kinases/metabolism ; Transcriptional Activation/genetics ; X-Linked Inhibitor of Apoptosis Protein/genetics ; X-Linked Inhibitor of Apoptosis Protein/metabolism ; Xenograft Model Antitumor Assays
Chemical Substances	Intracellular Signaling Peptides and Proteins ; NF-kappa B ; X-Linked Inhibitor of Apoptosis Protein ; XIAP protein, human ; Aldehyde Dehydrogenase (EC 1.2.1.3) ; MKNK1 protein, human (EC 2.7.1.-) ; EGFR protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2018-01-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-17-1667
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Article ; Online: Disulfiram (DSF) acts as a copper ionophore to induce copper-dependent oxidative stress and mediate anti-tumor efficacy in inflammatory breast cancer.

Allensworth, Jennifer L / Evans, Myron K / Bertucci, François / Aldrich, Amy J / Festa, Richard A / Finetti, Pascal / Ueno, Naoto T / Safi, Rachid / McDonnell, Donald P / Thiele, Dennis J / Van Laere, Steven / Devi, Gayathri R

Molecular oncology

2015 Volume 9, Issue 6, Page(s) 1155–1168

Abstract: Cancer cells often have increased levels of reactive oxygen species (ROS); however, acquisition of redox adaptive mechanisms allows for evasion of ROS-mediated death. Inflammatory breast cancer (IBC) is a distinct, advanced BC subtype characterized by ... ...

Abstract	Cancer cells often have increased levels of reactive oxygen species (ROS); however, acquisition of redox adaptive mechanisms allows for evasion of ROS-mediated death. Inflammatory breast cancer (IBC) is a distinct, advanced BC subtype characterized by high rates of residual disease and recurrence despite advances in multimodality treatment. Using a cellular model of IBC, we identified an oxidative stress response (OSR) signature in surviving IBC cells after administration of an acute dose of an ROS inducer. Metagene analysis of patient samples revealed significantly higher OSR scores in IBC tumor samples compared to normal or non-IBC tissues, which may contribute to the poor response of IBC tumors to common treatment strategies, which often rely heavily on ROS induction. To combat this adaptation, we utilized a potent redox modulator, the FDA-approved small molecule Disulfiram (DSF), alone and in combination with copper. DSF forms a complex with copper (DSF-Cu) increasing intracellular copper concentration both in vitro and in vivo, bypassing the need for membrane transporters. DSF-Cu antagonized NFκB signaling, aldehyde dehydrogenase activity and antioxidant levels, inducing oxidative stress-mediated apoptosis in multiple IBC cellular models. In vivo, DSF-Cu significantly inhibited tumor growth without significant toxicity, causing apoptosis only in tumor cells. These results indicate that IBC tumors are highly redox adapted, which may render them resistant to ROS-inducing therapies. DSF, through redox modulation, may be a useful approach to enhance chemo- and/or radio-sensitivity for advanced BC subtypes where therapeutic resistance is an impediment to durable responses to current standard of care.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Copper/metabolism ; Disulfiram/pharmacology ; Female ; Humans ; Inflammatory Breast Neoplasms/drug therapy ; Inflammatory Breast Neoplasms/genetics ; Inflammatory Breast Neoplasms/metabolism ; Ionophores/pharmacology ; Oxidative Stress/drug effects
Chemical Substances	Antineoplastic Agents ; Ionophores ; Copper (789U1901C5) ; Disulfiram (TR3MLJ1UAI)
Language	English
Publishing date	2015-02-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2415106-3
ISSN	1878-0261 ; 1574-7891
ISSN (online)	1878-0261
ISSN	1574-7891
DOI	10.1016/j.molonc.2015.02.007
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Article ; Online: Author Correction: Ybx1 fine-tunes PRC2 activities to control embryonic brain development.

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Article ; Online: Ybx1 fine-tunes PRC2 activities to control embryonic brain development.

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Article ; Online: Therapeutic HDAC inhibition in hypermutant diffuse intrinsic pontine glioma.

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Article ; Online: Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity.

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Article ; Online: Mn porphyrin in combination with ascorbate acts as a pro-oxidant and mediates caspase-independent cancer cell death.

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Article ; Online: XIAP Regulation by MNK Links MAPK and NFκB Signaling to Determine an Aggressive Breast Cancer Phenotype.

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Article ; Online: Disulfiram (DSF) acts as a copper ionophore to induce copper-dependent oxidative stress and mediate anti-tumor efficacy in inflammatory breast cancer.

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