Merkel cell polyomavirus activates LSD1-mediated blockade of non-canonical BAF to regulate transformation and tumorigenesis

Park, Donglim Esther; Cheng, Jingwei; McGrath, John P.; Lim, Matthew Y.; Cushman, Camille H.; Swanson, Selene K.; Tillgren, Michelle; Paulo, João A.; Gokhale, Prafulla C.; Florens, Laurence; Washburn, Michael P.; Trojer, Patrick; DeCaprio, James A.

doi:10.1038/s41556-020-0503-2

Cited by 58 publications

(72 citation statements)

References 69 publications

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“…New research has also identified a link between GBAF and Merkel cell carcinoma MCC disease progression. Within this cancer type, the histone demethylase Lysine-specific histone demethylase 1 (LSD1) has a role in maintaining MCC growth under both in vitro and in vivo conditions [ 133 ]. Park et al determined an antagonistic relationship exists between LSD1 and GBAF.…”

Section: Gbaf and Its Subunits In Mammalian Diseasementioning

confidence: 99%

“…Park et al determined an antagonistic relationship exists between LSD1 and GBAF. Interestingly, inhibition of LSD1 resulted in decreased MCC cell viability, but this effect was rescued by BRD9 inhibition [ 133 ]. BRD9 was also found to be essential for LSD1 target gene expression, as BRD9 degradation negatively affected LSD1 target gene induction.…”

Section: Gbaf and Its Subunits In Mammalian Diseasementioning

confidence: 99%

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GBAF, a small BAF sub-complex with big implications: a systematic review

Innis

Cabot

2020

Epigenetics & Chromatin

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ATP-dependent chromatin remodeling by histone-modifying enzymes and chromatin remodeling complexes is crucial for maintaining chromatin organization and facilitating gene transcription. In the SWI/SNF family of ATP-dependent chromatin remodelers, distinct complexes such as BAF, PBAF, GBAF, esBAF and npBAF/nBAF are of particular interest regarding their implications in cellular differentiation and development, as well as in various diseases. The recently identified BAF subcomplex GBAF is no exception to this, and information is emerging linking this complex and its components to crucial events in mammalian development. Furthermore, given the essential nature of many of its subunits in maintaining effective chromatin remodeling function, it comes as no surprise that aberrant expression of GBAF complex components is associated with disease development, including neurodevelopmental disorders and numerous malignancies. It becomes clear that building upon our knowledge of GBAF and BAF complex function will be essential for advancements in both mammalian reproductive applications and the development of more effective therapeutic interventions and strategies. Here, we review the roles of the SWI/SNF chromatin remodeling subcomplex GBAF and its subunits in mammalian development and disease.

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Section: Gbaf and Its Subunits In Mammalian Diseasementioning

confidence: 99%

Section: Gbaf and Its Subunits In Mammalian Diseasementioning

confidence: 99%

GBAF, a small BAF sub-complex with big implications: a systematic review

Innis

Cabot

2020

Epigenetics & Chromatin

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“…Recently, Park et al reported that the small T antigen, one of the oncogenic drivers of the Merkel cell polyomavirus, directly induces expression of LSD1‐CoREST complex members LSD1 and RCOR2, as well as of the transcription factor INSM1, which we identify as a target of LSD1. Intriguingly, they found that LSD1 and RCOR2 binding sites overlap with those of ATOH1, a key transcription factor of normal Merkel cell development (Bardot et al , 2013; Park et al , 2020). Other studies found that the inhibition of the T antigens induces cell cycle arrest (Houben et al , 2010) and induces neuronal differentiation when co‐cultured with keratinocytes (Harold et al , 2019).…”

Section: Discussionmentioning

confidence: 99%

LSD1 inhibition induces differentiation and cell death in Merkel cell carcinoma

et al. 2020

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Merkel cell carcinoma (MCC) is a highly aggressive, neuroendocrine skin cancer that lacks actionable mutations, which could be utilized for targeted therapies. Epigenetic regulators governing cell identity may represent unexplored therapeutic entry points. Here, we targeted epigenetic regulators in a pharmacological screen and discovered that the lysine‐specific histone demethylase 1A (LSD1/KDM1A) is required for MCC growth in vitro and in vivo. We show that LSD1 inhibition in MCC disrupts the LSD1‐CoREST complex leading to displacement and degradation of HMG20B (BRAF35), a poorly characterized complex member that is essential for MCC proliferation. Inhibition of LSD1 causes derepression of transcriptional master regulators of the neuronal lineage, activates a gene expression signature resembling normal Merkel cells, and induces cell cycle arrest and cell death. Our study unveils the importance of LSD1 for maintaining cellular plasticity and proliferation in MCC. There is also growing evidence that cancer cells exploit cellular plasticity and dedifferentiation programs to evade destruction by the immune system. The combination of LSD1 inhibitors with checkpoint inhibitors may thus represent a promising treatment strategy for MCC patients.

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“…These results suggest that the activities of HDAC1/2 may be critical in regulating CoREST repressor functions in RELA ependymoma. Recent work in small cell lung cancer (and Merkel cell carcinoma) also implicated that disrupting the CoREST complex, but not the inhibition of LSD1's enzymatic activities is required for blocking cancer cell proliferation 33 . Further studies identifying the components of the CoREST complex and identifying drugs that can disrupt the complex will be instrumental in developing an effective CoREST-targeted therapy for RELA ependymoma.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic 3D genome conformations identify novel therapeutic targets in ependymoma

Okonechnikov

Camgöz

Park

et al. 2020

Preprint

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Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial RELA-fusion associated group and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment1. Although the molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF (insulators) and H3K27ac (active enhancers) ChIP-seq as well as gene expression and whole-genome DNA methylation profiling in primary and relapsed ependymoma tumors and cell lines to identify chromosomal rearrangements and regulatory mechanisms underlying aberrant expression of genes that are essential for ependymoma tumorigenesis. In particular, we observe the formation of new topologically associating domains (‘neo-TADs’) by intra- and inter-chromosomal structural variants, tumor-specific 3D chromatin complexes of regulatory elements, and the replacement of CTCF insulators by DNA hyper-methylation as novel oncogenic mechanisms in ependymoma. Through inhibition experiments we validated that the newly identified genes, including RCOR2, ITGA6, LAMC1, and ARL4C, are highly essential for the survival of patient-derived ependymoma models in a disease subtype-specific manner. Thus, this study identifies potential novel therapeutic vulnerabilities in ependymoma and extends our ability to reveal tumor-dependency genes and pathways by oncogenic 3D genome conformations even in tumors that lack known genetic alterations.

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Merkel cell polyomavirus activates LSD1-mediated blockade of non-canonical BAF to regulate transformation and tumorigenesis

Cited by 58 publications

References 69 publications

GBAF, a small BAF sub-complex with big implications: a systematic review

GBAF, a small BAF sub-complex with big implications: a systematic review

LSD1 inhibition induces differentiation and cell death in Merkel cell carcinoma

Oncogenic 3D genome conformations identify novel therapeutic targets in ependymoma

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