Dataset Information

Lysine 68 acetylation directs MnSOD as a tetrameric detoxification complex versus a monomeric tumor promoter.

ABSTRACT: Manganese superoxide dismutase (MnSOD) functions as a tumor suppressor; however, once tumorigenesis occurs, clinical data suggest MnSOD levels correlate with more aggressive human tumors, implying a potential dual function of MnSOD in the regulation of metabolism. Here we show, using in vitro transformation and xenograft growth assays that the MnSOD-K68 acetylation (Ac) mimic mutant (MnSOD^K68Q) functions as a tumor promoter. Interestingly, in various breast cancer and primary cell types the expression of MnSOD^K68Q is accompanied with a change of MnSOD's stoichiometry from a known homotetramer complex to a monomeric form. Biochemical experiments using the MnSOD-K68Q Ac-mimic, or physically K68-Ac (MnSOD-K68-Ac), suggest that these monomers function as a peroxidase, distinct from the established MnSOD superoxide dismutase activity. MnSOD^K68Q expressing cells exhibit resistance to tamoxifen (Tam) and cells selected for Tam resistance exhibited increased K68-Ac and monomeric MnSOD. These results suggest a MnSOD-K68-Ac metabolic pathway for Tam resistance, carcinogenesis and tumor progression.

SUBMITTER: Zhu Y

PROVIDER: S-EPMC6546705 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Lysine 68 acetylation directs MnSOD as a tetrameric detoxification complex versus a monomeric tumor promoter.

Zhu Yueming Y Zou Xianghui X Dean Angela E AE Brien Joseph O' JO Gao Yucheng Y Tran Elizabeth L EL Park Seong-Hoon SH Liu Guoxiang G Kieffer Matthew B MB Jiang Haiyan H Stauffer Melissa E ME Hart Robert R Quan Songhua S Satchell Karla J F KJF Horikoshi Nobuo N Bonini Marcelo M Gius David D

Nature communications 20190603 1

Manganese superoxide dismutase (MnSOD) functions as a tumor suppressor; however, once tumorigenesis occurs, clinical data suggest MnSOD levels correlate with more aggressive human tumors, implying a potential dual function of MnSOD in the regulation of metabolism. Here we show, using in vitro transformation and xenograft growth assays that the MnSOD-K68 acetylation (Ac) mimic mutant (MnSOD<sup>K68Q</sup>) functions as a tumor promoter. Interestingly, in various breast cancer and primary cell typ ...[more]

PMID: 31160585

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Project description:BACKGROUND: Histone modifications play an important role in gene regulation. Acetylation of histone 3 lysine 9 (H3K9ac) is generally associated with transcription initiation and unfolded chromatin, thereby positively influencing gene expression. Deep sequencing of the 5' ends of gene transcripts using DeepCAGE delivers detailed information about the architecture and expression level of gene promoters. The combination of H3K9ac ChIP-chip and DeepCAGE in a myeloid leukemia cell line (THP-1) allowed us to study the spatial distribution of H3K9ac around promoters using a novel clustering approach. The promoter classes were analyzed for association with relevant genomic sequence features. RESULTS: We performed a clustering of 4,481 promoters according to their surrounding H3K9ac signal and analyzed the clustered promoters for association with different sequence features. The clustering revealed three groups with major H3K9ac signal upstream, centered and downstream of the promoter. Narrow single peak promoters tend to have a concentrated activity of H3K9ac in the upstream region, while broad promoters tend to have a concentrated activity of H3K9ac and RNA polymerase II binding in the centered and downstream regions. A subset of promoters with high gene expression level, compared to subsets with low and medium gene expression, shows dramatic increase in H3K9ac activity in the upstream cluster only; this may indicate that promoters in the centered and downstream clusters are predominantly regulated at post-initiation steps. Furthermore, the upstream cluster is depleted in CpG islands and more likely to regulate un-annotated genes. CONCLUSIONS: Clustering core promoters according to their surrounding acetylation signal is a promising approach for the study of histone modifications. When examining promoters clustered into groups according to their surrounding H3K9 acetylation signal, we find that the relative localization and intensity of H3K9ac is very specific depending on characteristic sequence features of the promoter. Experimental data from DeepCAGE and ChIP-chip experiments using undifferentiated (monocyte) and differentiated (macrophage) THP-1 cells leads us to the same conclusions.

Dataset Information

Lysine 68 acetylation directs MnSOD as a tetrameric detoxification complex versus a monomeric tumor promoter.

Publications

Lysine 68 acetylation directs MnSOD as a tetrameric detoxification complex versus a monomeric tumor promoter.

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