EP300 and SIRT1/6 Co-Regulate Lapatinib Sensitivity Via Modulating FOXO3-Acetylation and Activity in Breast Cancer

Cancers

Gyungyub Gong¹  HeeJin Lee¹  Ernesto Yagüe²  Zimam Mahmud²  Glowi Alasiri²  AnaR. Gomes²  Yannasittha Jiramongkol²  Stefania Zona²  Sathid Aimjongjun²  EricW.-F. Lam²  Shang Yao² 

[1] Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), Du Cane Road, London W12 0NN, UK;

关键词: acetylation;    breast cancer;    drug resistance;    EP300;    sirtuins;    FOXO3;    lapatinib;    post-translational modifications;   

DOI  :  10.3390/cancers11081067

来源: DOAJ

【 摘 要 】

Forkhead Box O3 (FOXO3) is a tumor 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-Lap^R) 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-Lap^R 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.

【 授权许可】

Unknown