BAP1 regulates epigenetic switch from pluripotency to differentiation in developmental lineages giving rise to BAP1-mutant cancers

Jeffim N. Kuznetsov, Tristan H. Aguero, Dawn A. Owens, Stefan Kurtenbach, Matthew G. Field, Michael A. Durante, Daniel A. Rodriguez, Mary Lou King, J. William Harbour

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Article numbereaax1738
JournalScience Advances
Volume5
Issue number9
DOIs
StatePublished - Sep 18 2019
Externally publishedYes

Fingerprint

switches
cancer
progressions
suppressors
phenotype
biology
genes
depletion
tumors
activation
modulation
causes
cells

ASJC Scopus subject areas

  • Physics and Astronomy (miscellaneous)
  • General

Cite this

BAP1 regulates epigenetic switch from pluripotency to differentiation in developmental lineages giving rise to BAP1-mutant cancers. / Kuznetsov, Jeffim N.; Aguero, Tristan H.; Owens, Dawn A.; Kurtenbach, Stefan; Field, Matthew G.; Durante, Michael A.; Rodriguez, Daniel A.; King, Mary Lou; William Harbour, J.

In: Science Advances, Vol. 5, No. 9, eaax1738, 18.09.2019.

Research output: Contribution to journalArticle

Kuznetsov, JN, Aguero, TH, Owens, DA, Kurtenbach, S, Field, MG, Durante, MA, Rodriguez, DA, King, ML & William Harbour, J 2019, 'BAP1 regulates epigenetic switch from pluripotency to differentiation in developmental lineages giving rise to BAP1-mutant cancers', Science Advances, vol. 5, no. 9, eaax1738. https://doi.org/10.1126/sciadv.aax1738
Kuznetsov, Jeffim N. ; Aguero, Tristan H. ; Owens, Dawn A. ; Kurtenbach, Stefan ; Field, Matthew G. ; Durante, Michael A. ; Rodriguez, Daniel A. ; King, Mary Lou ; William Harbour, J. / BAP1 regulates epigenetic switch from pluripotency to differentiation in developmental lineages giving rise to BAP1-mutant cancers. In: Science Advances. 2019 ; Vol. 5, No. 9.
@article{e0d479173fd44f70a07d9328063ec68b,
title = "BAP1 regulates epigenetic switch from pluripotency to differentiation in developmental lineages giving rise to BAP1-mutant cancers",
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.",
author = "Kuznetsov, {Jeffim N.} and Aguero, {Tristan H.} and Owens, {Dawn A.} and Stefan Kurtenbach and Field, {Matthew G.} and Durante, {Michael A.} and Rodriguez, {Daniel A.} and King, {Mary Lou} and {William Harbour}, J.",
year = "2019",
month = "9",
day = "18",
doi = "10.1126/sciadv.aax1738",
language = "English (US)",
volume = "5",
journal = "Indian Journal of Pure and Applied Physics",
issn = "0019-5596",
publisher = "National Institute of Science Communication and Information Resources (NISCAIR)",
number = "9",

}

TY - JOUR

T1 - BAP1 regulates epigenetic switch from pluripotency to differentiation in developmental lineages giving rise to BAP1-mutant cancers

AU - Kuznetsov, Jeffim N.

AU - Aguero, Tristan H.

AU - Owens, Dawn A.

AU - Kurtenbach, Stefan

AU - Field, Matthew G.

AU - Durante, Michael A.

AU - Rodriguez, Daniel A.

AU - King, Mary Lou

AU - William Harbour, J.

PY - 2019/9/18

Y1 - 2019/9/18

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85072323482&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072323482&partnerID=8YFLogxK

U2 - 10.1126/sciadv.aax1738

DO - 10.1126/sciadv.aax1738

M3 - Article

C2 - 31555735

AN - SCOPUS:85072323482

VL - 5

JO - Indian Journal of Pure and Applied Physics

JF - Indian Journal of Pure and Applied Physics

SN - 0019-5596

IS - 9

M1 - eaax1738

ER -