Altmetric

EP300 and SIRT1/6 co-regulate lapatinib sensitivity via modulating FOXO3-acetylation and activity in breast cancer

File Description SizeFormat 
EP300AndSIRT16CoRegulate.pdfPublished version6.53 MBAdobe PDFView/Open
Title: EP300 and SIRT1/6 co-regulate lapatinib sensitivity via modulating FOXO3-acetylation and activity in breast cancer
Authors: Mahmud, Z
Gomes, A
Lee, HJ
Aimjongjun, S
Jiramongkol, Y
Yao, S
Zona, S
Alasiri, G
Gong, G
Yague, E
Lam, E
Item Type: Journal Article
Abstract: Forkhead Box O3 (FOXO3) is a tumour suppressor whose activity is fine-tuned by post-translational modifications (PTMs). In this study, using the BT474 breast cancer cells and a recently established lapatinib resistant (BT474-LapR) cell line, we observed that higher FOXO3 and acetylated (Ac)-FOXO3 levels correlate with lapatinib sensitivity. Subsequent ectopic expression of EP300 led to an increase in acetylated-FOXO3 in sensitive, but not in resistant cells. Drug sensitivity assays revealed that sensitive BT474 cells show increased lapatinib cytotoxicity upon over-expression of wild-type but not acetylation-deficient EP300. Moreover, FOXO3 recruitment to target gene promoters is associated with target gene expression and drug response in sensitive cells, and the inability of FOXO3 to bind its target genes correlates with lapatinib-resistance in BT474-LapR cells. In addition, using SIRT1/6 specific siRNAs and chemical inhibitor, we also found that sirtuin 1 and -6 (SIRT1 and -6) play a part in fine-tuning FOXO3 acetylation and lapatinib sensitivity. Consistent with this, immunohistochemistry results from different breast cancer subtypes showed that high SIRT6/1 levels are associated with constitutive high FOXO3 expression which is related to FOXO3 deregulation/inactivation and poor prognosis in breast cancer patient samples. Collectively, our results suggest the involvement of FOXO3 acetylation in regulating lapatinib sensitivity of HER2-positive breast cancers.
Issue Date: 28-Jul-2019
Date of Acceptance: 25-Jul-2019
URI: http://hdl.handle.net/10044/1/72222
DOI: 10.3390/cancers11081067
ISSN: 2072-6694
Publisher: MDPI AG
Journal / Book Title: Cancers
Volume: 11
Issue: 8
Copyright Statement: © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Sponsor/Funder: Cancer Research UK
Breast Cancer Care & Breast Cancer Now
Commonwealth Scholarship Commission
Royal Embassy Of Saudi Arabia
Imperial College Trust
Breast Cancer Care & Breast Cancer Now
Medical Research Council (MRC)
Breast Cancer Care & Breast Cancer Now
Funder's Grant Number: 12011
2012NovemberPhD016
01094754
GLOWI ALI ESSA ALASIRI - B434
n/a
2012MayPR070
MR/N012097/1
2014NovPhD326
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
acetylation
breast cancer
drug resistance
EP300
sirtuins
FOXO3
lapatinib
post-translational modifications
FOXO TRANSCRIPTION FACTORS
GEFITINIB IRESSA
EXPRESSION
CELLS
PROTEINS
TARGET
OVEREXPRESSION
ACETYLATION
MECHANISMS
NETWORK
EP300
FOXO3
acetylation
breast cancer
drug resistance
lapatinib
post-translational modifications
sirtuins
1112 Oncology and Carcinogenesis
Publication Status: Published
Article Number: 1067
Appears in Collections:Department of Surgery and Cancer



Unless otherwise indicated, items in Spiral are protected by copyright and are licensed under a Creative Commons Attribution NonCommercial NoDerivatives License.

Creative Commons