Cholesterol Starvation and Hypoxia Activate the FVII Gene via the SREBP1-GILZ Pathway in Ovarian Cancer Cells to Produce Procoagulant Microvesicles
Shiro Koizume
1
Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan
,
Tomoko Takahashi
1
Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan
,
Mitsuyo Yoshihara
1
Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan
,
Yoshiyasu Nakamura
1
Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan
,
Wolfram Ruf
2
Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, Mainz, Germany
3
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States
,
Katsuya Takenaka
1
Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan
,
Etsuko Miyagi
4
Department of Obstetrics, Gynecology, and Molecular Reproductive Science, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
,
Yohei Miyagi
1
Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan
› InstitutsangabenFunding This work was partly supported by a grant from the Japanese Ministry of Education, Culture, Sports, Science and Technology [to S.K.].
Interaction between the transcription factors, hypoxia-inducible factor (HIF1α and HIF2α) and Sp1, mediates hypoxia-driven expression of FVII gene encoding coagulation factor VII (fVII) in ovarian clear cell carcinoma (CCC) cells. This mechanism is synergistically enhanced in response to serum starvation, a condition possibly associated with tumor hypoxia. This transcriptional response potentially results in venous thromboembolism, a common complication in cancer patients by producing procoagulant extracellular vesicles (EVs). However, which deficient serum factors are responsible for this characteristic transcriptional mechanism is unknown. Here, we report that cholesterol deficiency mediates synergistic FVII expression under serum starvation and hypoxia (SSH) via novel sterol regulatory element binding protein-1 (SREBP1)-driven mechanisms. Unlike conventional mechanisms, SREBP1 indirectly enhances FVII transcription through the induction of a new target, glucocorticoid-induced leucine zipper (GILZ) protein. GILZ expression induced in response to hypoxia by a HIF1α-dependent mechanism activates SREBP1 under SSH, suggesting reciprocal regulation between SREBP1 and GILZ. Furthermore, GILZ binds to the FVII locus. Xenograft tumor samples analyzed by chromatin immunoprecipitation confirmed that HIF1α-aryl hydrocarbon nuclear translocator and GILZ bind to the TSC22D3 (GILZ) and FVII gene loci, respectively, thereby potentially modulating chromatin function to augment FVII transcription. Thus, deficiency of both O2 and cholesterol, followed by interplay between HIFs, Sp1, and SREBP1-GILZ pathways synergistically induce fVII synthesis, resulting in the shedding of procoagulant EVs.
4
van den Berg YW,
Osanto S,
Reitsma PH,
Versteeg HH.
The relationship between tissue factor and cancer progression: insights from bench and bedside. Blood 2012; 119 (04) 924-932
6
Sharma S,
Zuñiga F,
Rice GE,
Perrin LC,
Hooper JD,
Salomon C.
Tumor-derived exosomes in ovarian cancer - liquid biopsies for early detection and real-time monitoring of cancer progression. Oncotarget 2017; 8 (61) 104687-104703
7
Koizume S,
Ito S,
Yoshioka Y.
, et al. High-level secretion of tissue factor-rich extracellular vesicles from ovarian cancer cells mediated by filamin-A and protease-activated receptors. Thromb Haemost 2016; 115 (02) 299-310
8
Yokota N,
Koizume S,
Miyagi E.
, et al. Self-production of tissue factor-coagulation factor VII complex by ovarian cancer cells. Br J Cancer 2009; 101 (12) 2023-2029
9
Koizume S,
Jin M-S,
Miyagi E.
, et al. Activation of cancer cell migration and invasion by ectopic synthesis of coagulation factor VII. Cancer Res 2006; 66 (19) 9453-9460
10
Koizume S,
Yokota N,
Miyagi E.
, et al. Hepatocyte nuclear factor-4-independent synthesis of coagulation factor VII in breast cancer cells and its inhibition by targeting selective histone acetyltransferases. Mol Cancer Res 2009; 7 (12) 1928-1936
11
Koizume S,
Ito S,
Miyagi E.
, et al. HIF2α-Sp1 interaction mediates a deacetylation-dependent FVII-gene activation under hypoxic conditions in ovarian cancer cells. Nucleic Acids Res 2012; 40 (12) 5389-5401
15
Koizume S,
Ito S,
Nakamura Y.
, et al. Lipid starvation and hypoxia synergistically activate ICAM1 and multiple genes in an Sp1-dependent manner to promote the growth of ovarian cancer. Mol Cancer 2015; 14: 77
16
Koizume S,
Miyagi Y.
Lipid droplets A key cellular organelle associated with cancer cell survival under normoxia and hypoxia. Int J Mol Sci 2016; 17 (09) 1430
19
Wang W-A,
Liu W-X,
Durnaoglu S.
, et al. Loss of calreticulin uncovers a critical role for calcium in regulating cellular lipid homeostasis. Sci Rep 2017; 7 (01) 5941
21
Yang T,
Espenshade PJ,
Wright ME.
, et al. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 2002; 110 (04) 489-500
22
Horton JD,
Goldstein JL,
Brown MS.
SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002; 109 (09) 1125-1131
28
Latasa M-J,
Moon YS,
Kim K-H,
Sul H-S.
Nutritional regulation of the fatty acid synthase promoter in vivo: sterol regulatory element binding protein functions through an upstream region containing a sterol regulatory element. Proc Natl Acad Sci U S A 2000; 97 (19) 10619-10624
29
Rome S,
Lecomte V,
Meugnier E.
, et al. Microarray analyses of SREBP-1a and SREBP-1c target genes identify new regulatory pathways in muscle. Physiol Genomics 2008; 34 (03) 327-337
30
Asselin-Labat ML,
David M,
Biola-Vidamment A.
, et al. GILZ, a new target for the transcription factor FoxO3, protects T lymphocytes from interleukin-2 withdrawal-induced apoptosis. Blood 2004; 104 (01) 215-223
31
Ronchetti S,
Migliorati G,
Riccardi C.
GILZ as a mediator of the anti-inflammatory effects of glucocorticoids. Front Endocrinol (Lausanne) 2015; 6: 170
34
Lim W,
Park C,
Shim MK,
Lee YH,
Lee YM,
Lee Y.
Glucocorticoids suppress hypoxia-induced COX-2 and hypoxia inducible factor-1α expression through the induction of glucocorticoid-induced leucine zipper. Br J Pharmacol 2014; 171 (03) 735-745
36
Wang Y,
Ma Y-Y,
Song X-L.
, et al. Upregulations of glucocorticoid-induced leucine zipper by hypoxia and glucocorticoid inhibit proinflammatory cytokines under hypoxic conditions in macrophages. J Immunol 2012; 188 (01) 222-229
38
Bené H,
Lasky D,
Ntambi JM.
Cloning and characterization of the human stearoyl-CoA desaturase gene promoter: transcriptional activation by sterol regulatory element binding protein and repression by polyunsaturated fatty acids and cholesterol. Biochem Biophys Res Commun 2001; 284 (05) 1194-1198
39
Koizume S,
Miyagi Y.
Breast cancer phenotypes regulated by tissue factor-factor VII pathway: possible therapeutic targets. World J Clin Oncol 2014; 5 (05) 908-920
40
Wurm T,
Wright DG,
Polakowski N,
Mesnard J-M,
Lemasson I.
The HTLV-1-encoded protein HBZ directly inhibits the acetyl transferase activity of p300/CBP. Nucleic Acids Res 2012; 40 (13) 5910-5925
41
Wright DG,
Marchal C,
Hoang K.
, et al. Human T-cell leukemia virus type-1-encoded protein HBZ represses p53 function by inhibiting the acetyltransferase activity of p300/CBP and HBO1. Oncotarget 2016; 7 (02) 1687-1706
42
Di Marco B,
Massetti M,
Bruscoli S.
, et al. Glucocorticoid-induced leucine zipper (GILZ)/NF-kappaB interaction: role of GILZ homo-dimerization and C-terminal domain. Nucleic Acids Res 2007; 35 (02) 517-528
43
Tan M,
Gu Q,
He H,
Pamarthy D,
Semenza GL,
Sun Y.
SAG/ROC2/RBX2 is a HIF-1 target gene that promotes HIF-1 α ubiquitination and degradation. Oncogene 2008; 27 (10) 1404-1411
44
Han Z-B,
Ren H,
Zhao H.
, et al. Hypoxia-inducible factor (HIF)-1 α directly enhances the transcriptional activity of stem cell factor (SCF) in response to hypoxia and epidermal growth factor (EGF). Carcinogenesis 2008; 29 (10) 1853-1861
45
Koizume S,
Miyagi Y.
Potential coagulation factor-driven pro-inflammatory responses in ovarian cancer tissues associated with insufficient O2 and plasma supply. Int J Mol Sci 2017; 18 (04) 809