title: FOXO1 is a TXN- and p300-dependent sensor and effector of oxidative stress in diffuse large B-cell lymphomas characterized by increased oxidative metabolism.
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.
authors.affiliation: Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: T
authors.initials: T
authors.lastname: Sewastianik
authors.affiliation: Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Szydlowski
authors.affiliation: Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: E
authors.initials: E
authors.lastname: Jablonska
authors.affiliation: Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: E
authors.initials: E
authors.lastname: Bialopiotrowicz
authors.affiliation: Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: P
authors.initials: P
authors.lastname: Kiliszek
authors.affiliation: Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: P
authors.initials: P
authors.lastname: Gorniak
authors.affiliation: Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Polak
authors.affiliation: Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Prochorec-Sobieszek
authors.affiliation: Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Szumera-Cieckiewicz
authors.affiliation: Department of Soft Condensed Matter, Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: T S
authors.initials: TS
authors.lastname: Kaminski
authors.affiliation: Department of Immunology, Maria Sklodowska-Curie Memorial Cancer Center-Institute of Oncology, Warsaw, Poland.
authors.forename: S
authors.initials: S
authors.lastname: Markowicz
authors.affiliation: Department of Immunology, Maria Sklodowska-Curie Memorial Cancer Center-Institute of Oncology, Warsaw, Poland.
authors.forename: E
authors.initials: E
authors.lastname: Nowak
authors.affiliation: Department of Immunology, Maria Sklodowska-Curie Memorial Cancer Center-Institute of Oncology, Warsaw, Poland.
authors.forename: M A
authors.initials: MA
authors.lastname: Grygorowicz
authors.affiliation: Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: K
authors.initials: K
authors.lastname: Warzocha
authors.affiliation: Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: P
authors.initials: P
authors.lastname: Juszczynski
mesh_terms: D000107:Acetylation; D017209:Apoptosis / Q000235:genetics; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D004734:Energy Metabolism; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D021381:Protein Transport; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000071161:Forkhead Box Protein O1; D051560:Proto-Oncogene Proteins c-bcl-6; D017382:Reactive Oxygen Species; C491203:TXN protein, human; D013879:Thioredoxins; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human