FOXO1 is a TXN- and p300-dependent sensor and effector of oxidative stress in diffuse large B-cell lymphomas characterized by increased oxidative metabolism

Tomasz Sewastianik , Maciej Szydlowski , Ewa Jablonska , Emilia Bialopiotrowicz , Przemysław Kiliszek , Patryk Gorniak , Anna Polak , Monika Prochorec-Sobieszek , Anna Szumera-Ciećkiewicz , TS. Kaminski , Sergiusz Markowicz , Eliza Nowak , Monika Grygorowicz , Krzysztof Warzocha , Przemysław Juszczyński

Abstract

Molecular profiling has led to identification of subtypes of diffuse large B-cell lymphomas (DLBCLs) differing in terms of oncogenic signaling and metabolic programs. The OxPhos-DLBCL subtype is characterized by enhanced mitochondrial oxidative phosphorylation. As increased oxidative metabolism leads to overproduction of potentially toxic reactive oxygen species (ROS), we sought to identify mechanisms responsible for adaptation of OxPhos cells to these conditions. Herein, we describe a mechanism involving the FOXO1-TXN-p300 redox-dependent circuit protecting OxPhos-DLBCL cells from ROS toxicity. We identify a BCL6-dependent transcriptional mechanism leading to relative TXN overexpression in OxPhos cells. We found that OxPhos cells lacking TXN were uniformly more sensitive to ROS and doxorubicin than control cells. Consistent with this, the overall survival of patients with high TXN mRNA expression, treated with doxorubicin-containing regimens, is significantly shorter than of those with low TXN mRNA expression. TXN overexpression curtails p300-mediated FOXO1 acetylation and its nuclear translocation in response to oxidative stress, thus attenuating FOXO1 transcriptional activity toward genes involved in apoptosis and cell cycle inhibition. We also demonstrate that FOXO1 knockdown in cells with silenced TXN expression markedly reduces ROS-induced apoptosis, indicating that FOXO1 is the major sensor and effector of oxidative stress in OxPhos-DLBCLs. These data highlight dynamic, context-dependent modulation of FOXO1 tumor-suppressor functions via acetylation and reveal potentially targetable vulnerabilities in these DLBCLs.
Publication typeOriginal work published in-full
Author Tomasz Sewastianik
Tomasz Sewastianik,,
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, Maciej Szydlowski
Maciej Szydlowski,,
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, Ewa Jablonska
Ewa Jablonska,,
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, Emilia Bialopiotrowicz
Emilia Bialopiotrowicz,,
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, Przemysław Kiliszek
Przemysław Kiliszek,,
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, Patryk Gorniak
Patryk Gorniak,,
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, Anna Polak
Anna Polak,,
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, Monika Prochorec-Sobieszek (COIW / ZPDL)
Monika Prochorec-Sobieszek,,
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, Anna Szumera-Ciećkiewicz (COIW / ZPDL / ZPDL-PKB)
Anna Szumera-Ciećkiewicz,,
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, TS. Kaminski
TS. Kaminski,,
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et al.`
Journal seriesOncogene, ISSN 0950-9232, (A 40 pkt)
Issue year2016
Vol35
No46
Pages5989-6000
Publication size in sheets0.55
Keywords in EnglishTRANSCRIPTION FACTOR; HYDROGEN-PEROXIDE; THIOREDOXIN; EXPRESSION; APOPTOSIS; SURVIVAL; INHIBITOR; PATHWAYS; CANCER; GENE
ASJC Classification1306 Cancer Research; 1311 Genetics; 1312 Molecular Biology
DOIDOI:10.1038/onc.2016.126
URL http://www.nature.com/onc/journal/vaop/ncurrent/full/onc2016126a.html
Languageen angielski
Score (nominal)40
Score sourcejournalList
ScoreMinisterial score = 40.0, 15-05-2020, ArticleFromJournal
Ministerial score (2013-2016) = 40.0, 15-05-2020, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2016 = 1.597; WoS Impact Factor: 2016 = 7.519 (2) - 2016=7.272 (5)
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