Regulation of hypoxia-inducible factor functions in the nucleus by sphingosine-1-phosphate

doi:10.1096/fj.201901734RR

	Regulation of hypoxia-inducible factor functions in the nucleus by sphingosine-1-phosphate
	Hait, Nitai C.3,4,5; Maiti, Aparna 3,4,5; Xu, Pan 1,6; Qi, Qianya 2; Kawaguchi, Tsutomu 3,4; Okano, Maiko 3,4; Takabe, Kazuaki 3,4; Yan, Li 2; Luo, Cheng 1,6
刊名	FASEB JOURNAL
	2020-02-04
页码	18
关键词	hypoxia-inducible factors sphingosine-1-phosphate sphingosine kinase 2 triple-negative breast cancer
ISSN号	0892-6638
DOI	10.1096/fj.201901734RR
通讯作者	Hait, Nitai C.(nitai.hait@roswellpark.org)
英文摘要	Sphingosine kinase 2 (SphK2) is known to phosphorylate the nuclear sphingolipid metabolite to generate sphingosine-1-phosphate (S1P). Nuclear S1P is involved in epigenetic regulation of gene expression; however, the underlying mechanisms are not well understood. In this work, we have identified the role of nuclear S1P and SphK2 in regulating hypoxia-responsive master transcription factors hypoxia-inducible factor (HIF)-1 alpha/2 alpha, and their functions in breast cancer, with a focus on triple-negative breast cancer (TNBC). We have shown SphK2 is associated with HIF-1 alpha in protein complexes, and is enriched at the promoters of HIF target genes, including vascular endothelial growth factor (VEGF), where it enhances local histone H3 acetylation and transcription. S1P specifically binds to the PAS domains of HIF-1 alpha. SphK2, and HIF-1 alpha expression levels are elevated in metastatic estrogen receptor-positive (ER+) and TNBC clinical tissue specimens compared to healthy breast tissue samples. To determine if S1P formation in the nucleus by SphK2 is a key regulator of HIF functions, we found using a preclinical TNBC xenograft mouse model, and an existing selective SphK2 inhibitor K-145, that nuclear S1P, histone acetylation, HIF-1 alpha expression, and TNBC tumor growth were all reduced in vivo. Our results suggest that S1P and SphK2 in the nucleus are linked to the regulation of HIF-1 alpha/2 alpha functions associated with breast cancer progression, and may provide potential therapeutic targets.
资助项目	Roswell Park Cancer Institute (RPCI)[714084-01]
WOS关键词	SPHINGOSINE KINASE 2 ; BREAST-CANCER ; HISTONE ACETYLATION ; EXPRESSION ; PROTEIN ; SPHK2 ; GROWTH ; ACID ; CHEMORESISTANCE ; OVEREXPRESSION
WOS研究方向	Biochemistry & Molecular Biology ; Life Sciences & Biomedicine - Other Topics ; Cell Biology
语种	英语
出版者	FEDERATION AMER SOC EXP BIOL
WOS记录号	WOS:000511114000001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/281695]
专题	中国科学院上海药物研究所
通讯作者	Hait, Nitai C.
作者单位	1.Chinese Acad Sci, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai, Peoples R China 2.Roswell Park Comprehens Canc Ctr, Dept Biostat & Bioinformat, Buffalo, NY USA 3.Roswell Park Comprehens Canc Ctr, Div Breast Surg, Buffalo, NY USA 4.Roswell Park Comprehens Canc Ctr, Dept Surg Oncol, Buffalo, NY USA 5.Roswell Park Comprehens Canc Ctr, Dept Mol & Cellular Biol, Elm & Carlton St, Buffalo, NY 14263 USA 6.Univ Chinese Acad Sci, Sch Pharm, Beijing, Peoples R China
推荐引用方式 GB/T 7714	Hait, Nitai C.,Maiti, Aparna,Xu, Pan,et al. Regulation of hypoxia-inducible factor functions in the nucleus by sphingosine-1-phosphate[J]. FASEB JOURNAL,2020:18.
APA	Hait, Nitai C..,Maiti, Aparna.,Xu, Pan.,Qi, Qianya.,Kawaguchi, Tsutomu.,...&Luo, Cheng.(2020).Regulation of hypoxia-inducible factor functions in the nucleus by sphingosine-1-phosphate.FASEB JOURNAL,18.
MLA	Hait, Nitai C.,et al."Regulation of hypoxia-inducible factor functions in the nucleus by sphingosine-1-phosphate".FASEB JOURNAL (2020):18.