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

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...

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Veröffentlicht in:	Scientific reports 2020-10, Vol.10 (1), p.16992-16992, Article 16992
Hauptverfasser:	Barkovskaya, Anna, Seip, Kotryna, Prasmickaite, Lina, Mills, Ian G., Moestue, Siver A., Itkonen, Harri M.
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Schlagworte:	631/337 631/337/100 631/337/176 631/337/572 631/45 631/45/221 631/67 631/67/1347 692/53 692/53/2423 Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Antineoplastic Agents - therapeutic use Breast Neoplasms - drug therapy Breast Neoplasms - mortality Drug Resistance, Neoplasm ErbB Receptors - metabolism Female Gene Expression Profiling Gene Expression Regulation, Neoplastic Humanities and Social Sciences Humans MCF-7 Cells multidisciplinary N-Acetylglucosaminyltransferases - genetics N-Acetylglucosaminyltransferases - metabolism RNA, Small Interfering - genetics Science Science (multidisciplinary) Signal Transduction Survival Analysis Tamoxifen - therapeutic use Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Unfolded Protein Response
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description	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.
doi_str_mv	10.1038/s41598-020-74083-z
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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). 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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). 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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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>33046784</pmid><doi>10.1038/s41598-020-74083-z</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record>
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subjects	631/337 631/337/100 631/337/176 631/337/572 631/45 631/45/221 631/67 631/67/1347 692/53 692/53/2423 Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Antineoplastic Agents - therapeutic use Breast Neoplasms - drug therapy Breast Neoplasms - mortality Drug Resistance, Neoplasm ErbB Receptors - metabolism Female Gene Expression Profiling Gene Expression Regulation, Neoplastic Humanities and Social Sciences Humans MCF-7 Cells multidisciplinary N-Acetylglucosaminyltransferases - genetics N-Acetylglucosaminyltransferases - metabolism RNA, Small Interfering - genetics Science Science (multidisciplinary) Signal Transduction Survival Analysis Tamoxifen - therapeutic use Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Unfolded Protein Response
title	Inhibition of O-GlcNAc transferase activates tumor-suppressor gene expression in tamoxifen-resistant breast cancer cells
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