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Protein acyltransferase DHHC3 regulates breast tumor growth, oxidative stress and senescence.

ABSTRACT: Protein acyltransferase DHHC3 is upregulated in malignant and metastatic human breast cancer, and its elevated expression correlates with diminished survival not only in human breast cancer but also in six other cancer types. In a direct demonstration of pro-tumor DHHC3 function, ZDHHC3 ablation diminished both MDA-MB-231 mammary cell xenografts growth and the size of metastatic lung colonies. Gene array data and fluorescence dye assays documented increased oxidative stress and senescence in ZDHHC3-ablated cells. Consistent with increased senescence, ZDHHC3-ablated tumors showed enhanced recruitment of innate immune cells (anti-tumor macrophages, NK cells) associated with clearance of senescent tumors. ZDHHC3-ablation effects (decreased tumor growth, increased oxidative stress, increased senescence) were reversed upon reconstitution with wildtype, but not enzyme active site-deficient DHHC3. ZDHHC3-ablation effects on oxidative stress/senescence were also substantially reversed upon concomitant ablation of upregulated oxidative stress driver TXNIP. Diminished DHHC3-dependent palmitoylation of ERGIC3 protein likely plays a key role in TXNIP upregulation. In conclusion, through its palmitoylation activity, DHHC3 supports in vivo breast tumor growth by a mechanism involving negative modulation of tumor cell oxidative stress and senescence.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE102776 | GEO | 2017/08/18

SECONDARY ACCESSION(S): PRJNA398659

REPOSITORIES: GEO

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Project description:DallePazze2014 - Cellular senescene-induced mitochondrial dysfunction This model is described in the article: Dynamic modelling of pathways to cellular senescence reveals strategies for targeted interventions. Dalle Pezze P, Nelson G, Otten EG, Korolchuk VI, Kirkwood TB, von Zglinicki T, Shanley DP. PLoS Comput. Biol. 2014 Aug; 10(8): e1003728 Abstract: Cellular senescence, a state of irreversible cell cycle arrest, is thought to help protect an organism from cancer, yet also contributes to ageing. The changes which occur in senescence are controlled by networks of multiple signalling and feedback pathways at the cellular level, and the interplay between these is difficult to predict and understand. To unravel the intrinsic challenges of understanding such a highly networked system, we have taken a systems biology approach to cellular senescence. We report a detailed analysis of senescence signalling via DNA damage, insulin-TOR, FoxO3a transcription factors, oxidative stress response, mitochondrial regulation and mitophagy. We show in silico and in vitro that inhibition of reactive oxygen species can prevent loss of mitochondrial membrane potential, whilst inhibition of mTOR shows a partial rescue of mitochondrial mass changes during establishment of senescence. Dual inhibition of ROS and mTOR in vitro confirmed computational model predictions that it was possible to further reduce senescence-induced mitochondrial dysfunction and DNA double-strand breaks. However, these interventions were unable to abrogate the senescence-induced mitochondrial dysfunction completely, and we identified decreased mitochondrial fission as the potential driving force for increased mitochondrial mass via prevention of mitophagy. Dynamic sensitivity analysis of the model showed the network stabilised at a new late state of cellular senescence. This was characterised by poor network sensitivity, high signalling noise, low cellular energy, high inflammation and permanent cell cycle arrest suggesting an unsatisfactory outcome for treatments aiming to delay or reverse cellular senescence at late time points. Combinatorial targeted interventions are therefore possible for intervening in the cellular pathway to senescence, but in the cases identified here, are only capable of delaying senescence onset. This model is hosted on BioModels Database and identified by: BIOMD0000000582. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Protein acyltransferase DHHC3 regulates breast tumor growth, oxidative stress and senescence.

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