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XB-ART-56327
Sci Adv 2019 Sep 18;59:eaax1738. doi: 10.1126/sciadv.aax1738.
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BAP1 regulates epigenetic switch from pluripotency to differentiation in developmental lineages giving rise to BAP1-mutant cancers.

Kuznetsov JN , Aguero TH , Owens DA , Kurtenbach S , Field MG , Durante MA , Rodriguez DA , King ML , Harbour JW .


Abstract
The BAP1 tumor suppressor is mutated in many human cancers such as uveal melanoma, leading to poor patient outcome. It remains unclear how BAP1 functions in normal biology or how its loss promotes cancer progression. Here, we show that Bap1 is critical for commitment to ectoderm, mesoderm, and neural crest lineages during Xenopus laevis development. Bap1 loss causes transcriptional silencing and failure of H3K27ac to accumulate at promoters of key genes regulating pluripotency-to-commitment transition, similar to findings in uveal melanoma. The Bap1-deficient phenotype can be rescued with human BAP1, by pharmacologic inhibition of histone deacetylase (HDAC) activity or by specific knockdown of Hdac4. Similarly, BAP1-deficient uveal melanoma cells are preferentially vulnerable to HDAC4 depletion. These findings show that Bap1 regulates lineage commitment through H3K27ac-mediated transcriptional activation, at least in part, by modulation of Hdac4, and they provide insights into how BAP1 loss promotes cancer progression.

PubMed ID: 31555735
PMC ID: PMC6750916
Article link: Sci Adv
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: bap1 ctrl dct foxd3 fzd7 hdac4 msx1 myod1 otx2 pax2 pou5f3.2 rax rbpms rpe sox10 sox2 tbxt vegt ventx2.2 zic1
Antibodies: HIST1H2AA Ab1 h3-3a Ab41 h3-3a Ab42 h3-3a Ab43
Morpholinos: asxl1 MO1 asxl1 MO2 bap1 MO1 bap1 MO2 bap1 cMO1 bmi1 MO1 hdac3 MO1 hdac4 MO1 hdac4 MO2

Disease Ontology terms: uveal melanoma
GEO Series: GSE126597: NCBI
GSE126598: NCBI
GSE126599: NCBI

Article Images: [+] show captions
References [+] :
Agüero, Indian hedgehog signaling is required for proper formation, maintenance and migration of Xenopus neural crest. 2012, Pubmed, Xenbase