Inhibition of O-GlcNAc transferase activates tumor-suppressor gene expression in tamoxifen-resistant breast cancer cells

Autor:	Lina Prasmickaite, Harri M. Itkonen, Ian G. Mills, Anna Barkovskaya, Kotryna Seip, Siver Andreas Moestue
Přispěvatelé:	Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki
Jazyk:	angličtina
Rok vydání:	2020
Předmět:	Molecular biology Glycobiology Estrogen receptor lcsh:Medicine MYC Biochemistry PATHWAY 0302 clinical medicine Breast cancer GLCNACYLATION RNA Small Interfering skin and connective tissue diseases lcsh:Science Cancer Regulation of gene expression 0303 health sciences Multidisciplinary Chromatin 3. Good health ErbB Receptors Gene Expression Regulation Neoplastic 030220 oncology & carcinogenesis MCF-7 Cells Female Epigenetics Signal transduction Transcription hormones hormone substitutes and hormone antagonists medicine.drug Signal Transduction Tumor suppressor gene DATABASE Antineoplastic Agents Breast Neoplasms Biology METABOLISM N-Acetylglucosaminyltransferases Predictive markers Article MECHANISMS 03 medical and health sciences SDG 3 - Good Health and Well-being Medisinske Fag: 700 [VDP] medicine OGT ACTIVITY Humans Transcription factor 030304 developmental biology Adaptor Proteins Signal Transducing Gene Expression Profiling Tumor Suppressor Proteins lcsh:R DRIVEN N-ACETYLGLUCOSAMINE Survival Analysis Gene expression profiling Tamoxifen Drug Resistance Neoplasm Cancer research Unfolded Protein Response lcsh:Q 3111 Biomedicine Biomarkers
Zdroj:	Scientific Reports, Vol 10, Iss 1, Pp 1-10 (2020) Scientific Reports Barkovskaya, A, Seip, K, Prasmickaite, L, Mills, I G, Moestue, S A & Itkonen, H M 2020, ' Inhibition of O-GlcNAc transferase activates tumor-suppressor gene expression in tamoxifen-resistant breast cancer cells ', Scientific Reports, vol. 10, no. 1 . https://doi.org/10.1038/s41598-020-74083-z
ISSN:	2045-2322
DOI:	10.1038/s41598-020-74083-z
Popis:	In this study, we probed the importance of O-GlcNAc transferase (OGT) activity for the survival of tamoxifen-sensitive (TamS) and tamoxifen-resistant (TamR) breast cancer cells. Tamoxifen is an antagonist of estrogen receptor (ERα), a transcription factor expressed in over 50% of breast cancers. ERα-positive breast cancers are successfully treated with tamoxifen; however, a significant number of patients develop tamoxifen-resistant disease. We show that in vitro development of tamoxifen-resistance is associated with increased sensitivity to the OGT small molecule inhibitor OSMI-1. Global transcriptome profiling revealed that TamS cells adapt to OSMI-1 treatment by increasing the expression of histone genes. This is known to mediate chromatin compaction. In contrast, TamR cells respond to OGT inhibition by activating the unfolded protein response and by significantly increasing ERRFI1 expression. ERRFI1 is an endogenous inhibitor of ERBB-signaling, which is a known driver of tamoxifen-resistance. We show that ERRFI1 is selectively downregulated in ERα-positive breast cancers and breast cancers driven by ERBB2. This likely occurs via promoter methylation. Finally, we show that increased ERRFI1 expression is associated with extended survival in patients with ERα-positive tumors (p = 9.2e−8). In summary, we show that tamoxifen-resistance is associated with sensitivity to OSMI-1, and propose that this is explained in part through an epigenetic activation of the tumor-suppressor ERRFI1 in response to OSMI-1 treatment. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Databáze:	OpenAIRE
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