Acetylated H4K16 by MYST1 protects UROtsa cells from arsenic toxicity and is decreased following chronic arsenic exposure.
Arsenic, a human carcinogen that is associated with an increased risk of bladder cancer, is commonly found in drinking water. An important mechanism by which arsenic is thought to be carcinogenic is through the induction of epigenetic changes that lead to aberrant gene expression. Previously, we reported that the SAS2 gene is required for optimal growth of yeast in the presence of arsenite (As(III)). Yeast Sas2p is orthologous to human MYST1, a histone 4 lysine 16 (H4K16) acetyltransferase. Here, we show that H4K16 acetylation is necessary for the resistance of yeast to As(III) through the modulation of chromatin state. We further explored the role of MYST1 and H4K16 acetylation in arsenic toxicity and carcinogenesis in human bladder epithelial cells. The expression of MYST1 was knocked down in UROtsa cells, a model of bladder epithelium that has been used to study arsenic-induced carcinogenesis. Silencing of MYST1 reduced acetylation of H4K16 and induced sensitivity to As(III) and to its more toxic metabolite monomethylarsonous acid (MMA(III)) at doses relevant to high environmental human exposures. In addition, both As(III) and MMA(III) treatments decreased global H4K16 acetylation levels in a dose- and time-dependent manner. This indicates that acetylated H4K16 is required for resistance to arsenic and that a reduction in its levels as a consequence of arsenic exposure may contribute to toxicity in UROtsa cells. Based on these findings, we propose a novel role for the MYST1 gene in human sensitivity to arsenic.
Jo
William Jaime
WJ
Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, CA 94720, USA. williamjo@berkeley.edu
Ren
Xuefeng
X
Chu
Feixia
F
Aleshin
Maria
M
Wintz
Henri
H
Burlingame
Alma
A
Smith
Martyn Thomas
MT
Vulpe
Chris Dillon
CD
Zhang
Luoping
L
D000107:Acetylation; D001152:Arsenicals; D015153:Blotting, Western; D002843:Chromatin / Q000502:physiology; D004396:Coloring Agents; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D020868:Gene Silencing / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D013058:Mass Spectrometry; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000254:growth & development; D013778:Tetrazolium Salts; D013844:Thiazoles; D001743:Urinary Bladder / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D001152:Arsenicals; D002843:Chromatin; D004396:Coloring Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; D051548:Histone Acetyltransferases; C496552:KAT8 protein, human; C022616:thiazolyl blue