Jae Kyo Yi

Correction: Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain.

PLoS Genet 2018 01 23;14(1):e1007190. Epub 2018 Jan 23.

[This corrects the article DOI: 10.1371/journal.pgen.1005591.].

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http://dx.doi.org/10.1371/journal.pgen.1007190	DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5779643	PMC

January 2018

Alkaline Ceramidase 1 Protects Mice from Premature Hair Loss by Maintaining the Homeostasis of Hair Follicle Stem Cells.

Authors:

Chih-Li Lin Ruijuan Xu Jae Kyo Yi Fang Li Jiang Chen Evan C Jones Jordan B Slutsky Liqun Huang Basil Rigas Jian Cao Xiaoming Zhong Ashley J Snider Lina M Obeid Yusuf A Hannun Cungui Mao

Stem Cell Reports 2017 11 19;9(5):1488-1500. Epub 2017 Oct 19.

Department of Medicine, Stony Brook University, Stony Brook, NY, USA; Department of Medicine and Stony Brook Cancer Center, Stony Brook University, HSC T15-023, Stony Brook, NY 11794, USA; Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY, USA; Department of Dermatology, Stony Brook University, Stony Brook, NY, USA. Electronic address:

Ceramides and their metabolites are important for the homeostasis of the epidermis, but much remains unknown about the roles of specific pathways of ceramide metabolism in skin biology. With a mouse model deficient in the alkaline ceramidase (Acer1) gene, we demonstrate that ACER1 plays a key role in the homeostasis of the epidermis and its appendages by controlling the metabolism of ceramides. Loss of Acer1 elevated the levels of various ceramides and sphingoid bases in the skin and caused progressive hair loss in mice. Mechanistic studies revealed that loss of Acer1 widened follicular infundibulum and caused progressive loss of hair follicle stem cells (HFSCs) due to reduced survival and stemness. These results suggest that ACER1 plays a key role in maintaining the homeostasis of HFSCs, and thereby the hair follicle structure and function, by regulating the metabolism of ceramides in the epidermis.

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http://dx.doi.org/10.1016/j.stemcr.2017.09.015	DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829345	PMC

November 2017

Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells.

Authors:

Jennifer Y Chen Benjamin Newcomb Chan Zhou Joshua V Pondick Sarani Ghoshal Samuel R York Daniel L Motola Nicolas Coant Jae Kyo Yi Cungui Mao Kenneth K Tanabe Irina Bronova Evgeny V Berdyshev Bryan C Fuchs Yusuf Hannun Raymond T Chung Alan C Mullen

Sci Rep 2017 03 21;7:44867. Epub 2017 Mar 21.

Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA.

Activation of hepatic stellate cells (HSCs) in response to injury is a key step in hepatic fibrosis, and is characterized by trans-differentiation of quiescent HSCs to HSC myofibroblasts, which secrete extracellular matrix proteins responsible for the fibrotic scar. There are currently no therapies to directly inhibit hepatic fibrosis. We developed a small molecule screen to identify compounds that inactivate human HSC myofibroblasts through the quantification of lipid droplets. We screened 1600 compounds and identified 21 small molecules that induce HSC inactivation. Four hits were tricyclic antidepressants (TCAs), and they repressed expression of pro-fibrotic factors Alpha-Actin-2 (ACTA2) and Alpha-1 Type I Collagen (COL1A1) in HSCs. RNA sequencing implicated the sphingolipid pathway as a target of the TCAs. Indeed, TCA treatment of HSCs promoted accumulation of ceramide through inhibition of acid ceramidase (aCDase). Depletion of aCDase also promoted accumulation of ceramide and was associated with reduced COL1A1 expression. Treatment with B13, an inhibitor of aCDase, reproduced the antifibrotic phenotype as did the addition of exogenous ceramide. Our results show that detection of lipid droplets provides a robust readout to screen for regulators of hepatic fibrosis and have identified a novel antifibrotic role for ceramide.

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http://dx.doi.org/10.1038/srep44867	DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359599	PMC

March 2017

Aging-related elevation of sphingoid bases shortens yeast chronological life span by compromising mitochondrial function.

Authors:

Jae Kyo Yi Ruijuan Xu Eunmi Jeong Izolda Mileva Jean-Philip Truman Chih-Li Lin Kai Wang Justin Snider Sally Wen Lina M Obeid Yusuf A Hannun Cungui Mao

Oncotarget 2016 Apr;7(16):21124-44

Department of Medicine, Stony Brook University, Stony Brook, NY, USA.

Sphingoid bases (SBs) as bioactive sphingolipids, have been implicated in aging in yeast. However, we know neither how SBs are regulated during yeast aging nor how they, in turn, regulate it. Herein, we demonstrate that the yeast alkaline ceramidases (YPC1 and YDC1) and SB kinases (LCB4 and LCB5) cooperate in regulating SBs during the aging process and that SBs shortens chronological life span (CLS) by compromising mitochondrial functions. With a lipidomics approach, we found that SBs were increased in a time-dependent manner during yeast aging. We also demonstrated that among the enzymes known for being responsible for the metabolism of SBs, YPC1 was upregulated whereas LCB4/5 were downregulated in the course of aging. This inverse regulation of YPC1 and LCB4/5 led to the aging-related upregulation of SBs in yeast and a reduction in CLS. With the proteomics-based approach (SILAC), we revealed that increased SBs altered the levels of proteins related to mitochondria. Further mechanistic studies demonstrated that increased SBs inhibited mitochondrial fusion and caused fragmentation, resulting in decreases in mtDNA copy numbers, ATP levels, mitochondrial membrane potentials, and oxygen consumption. Taken together, these results suggest that increased SBs mediate the aging process by impairing mitochondrial structural integrity and functions.

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http://dx.doi.org/10.18632/oncotarget.8195	DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008273	PMC

April 2016

Deficiency of the alkaline ceramidase ACER3 manifests in early childhood by progressive leukodystrophy.

Authors:

Simon Edvardson Jae Kyo Yi Chaim Jalas Ruijuan Xu Bryn D Webb Justin Snider Anastasia Fedick Elisheva Kleinman Nathan R Treff Cungui Mao Orly Elpeleg

J Med Genet 2016 06 20;53(6):389-96. Epub 2016 Jan 20.

The Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.

Background/aims: Leukodystrophies due to abnormal production of myelin cause extensive morbidity in early life; their genetic background is still largely unknown. We aimed at reaching a molecular diagnosis in Ashkenazi-Jewish patients who suffered from developmental regression at 6-13 months, leukodystrophy and peripheral neuropathy.

Methods: Exome analysis, determination of alkaline ceramidase activity catalysing the conversion of C18:1-ceramide to sphingosine and D-ribo-C12-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) (NBD)-phytoceramide to NBD-C12-fatty acid using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and thin layer chromatography, respectively, and sphingolipid analysis in patients' blood by LC-MS/MS.

Results: The patients were homozygous for p.E33G in the ACER3, which encodes a C18:1-alkaline ceramidase and C20:1-alkaline ceramidase. The mutation abolished ACER3 catalytic activity in the patients' cells and failed to restore alkaline ceramidase activity in yeast mutant strain. The levels of ACER3 substrates, C18:1-ceramides and dihydroceramides and C20:1-ceramides and dihydroceramides and other long-chain ceramides and dihydroceramides were markedly increased in the patients' plasma, along with that of complex sphingolipids, including monohexosylceramides and lactosylceramides.

Conclusions: Homozygosity for the p.E33G mutation in the ACER3 gene results in inactivation of ACER3, leading to the accumulation of various sphingolipids in blood and probably in brain, likely accounting for this new form of childhood leukodystrophy.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068917	PMC
http://dx.doi.org/10.1136/jmedgenet-2015-103457	DOI Listing

June 2016

Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain.

PLoS Genet 2015 Oct 16;11(10):e1005591. Epub 2015 Oct 16.

Department of Medicine, Stony Brook University, Stony Brook, New York, United States of America; Stony Brook Cancer Center, Stony Brook, New York, United States of America.

Dyshomeostasis of both ceramides and sphingosine-1-phosphate (S1P) in the brain has been implicated in aging-associated neurodegenerative disorders in humans. However, mechanisms that maintain the homeostasis of these bioactive sphingolipids in the brain remain unclear. Mouse alkaline ceramidase 3 (Acer3), which preferentially catalyzes the hydrolysis of C18:1-ceramide, a major unsaturated long-chain ceramide species in the brain, is upregulated with age in the mouse brain. Acer3 knockout causes an age-dependent accumulation of various ceramides and C18:1-monohexosylceramide and abolishes the age-related increase in the levels of sphingosine and S1P in the brain; thereby resulting in Purkinje cell degeneration in the cerebellum and deficits in motor coordination and balance. Our results indicate that Acer3 plays critically protective roles in controlling the homeostasis of various sphingolipids, including ceramides, sphingosine, S1P, and certain complex sphingolipids in the brain and protects Purkinje cells from premature degeneration.

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http://dx.doi.org/10.1371/journal.pgen.1005591	DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608763	PMC

October 2015

Tumor Necrosis Factor-α (TNFα)-induced Ceramide Generation via Ceramide Synthases Regulates Loss of Focal Adhesion Kinase (FAK) and Programmed Cell Death.

Authors:

María José Hernández-Corbacho Daniel Canals Mohamad M Adada Mengling Liu Can E Senkal Jae Kyo Yi Cungui Mao Chiara Luberto Yusuf A Hannun Lina M Obeid

J Biol Chem 2015 Oct 28;290(42):25356-73. Epub 2015 Aug 28.

From the Stony Brook Cancer Center, the Department of Medicine, and the Northport Veterans Affairs Medical Center, Northport, New York 11768

Ceramide synthases (CerS1-CerS6), which catalyze the N-acylation of the (dihydro)sphingosine backbone to produce (dihydro)ceramide in both the de novo and the salvage or recycling pathway of ceramide generation, have been implicated in the control of programmed cell death. However, the regulation of the de novo pathway compared with the salvage pathway is not fully understood. In the current study, we have found that late accumulation of multiple ceramide and dihydroceramide species in MCF-7 cells treated with TNFα occurred by up-regulation of both pathways of ceramide synthesis. Nevertheless, fumonisin B1 but not myriocin was able to protect from TNFα-induced cell death, suggesting that ceramide synthase activity is crucial for the progression of cell death and that the pool of ceramide involved derives from the salvage pathway rather than de novo biosynthesis. Furthermore, compared with control cells, TNFα-treated cells exhibited reduced focal adhesion kinase and subsequent plasma membrane permeabilization, which was blocked exclusively by fumonisin B1. In addition, exogenously added C6-ceramide mimicked the effects of TNFα that lead to cell death, which were inhibited by fumonisin B1. Knockdown of individual ceramide synthases identified CerS6 and its product C16-ceramide as the ceramide synthase isoform essential for the regulation of cell death. In summary, our data suggest a novel role for CerS6/C16-ceramide as an upstream effector of the loss of focal adhesion protein and plasma membrane permeabilization, via the activation of caspase-7, and identify the salvage pathway as the critical mechanism of ceramide generation that controls cell death.

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http://dx.doi.org/10.1074/jbc.M115.658658	DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646185	PMC

October 2015

Phosphorylation of p90RSK is associated with increased response to neoadjuvant chemotherapy in ER-positive breast cancer.

Authors:

Hyeong-Gon Moon Jae Kyo Yi Hee Sung Kim Hea Young Lee Kyung-Min Lee Minju Yi Sookyung Ahn Hee-Chul Shin Ji-hyun Ju Incheol Shin Wonshik Han Dong-Young Noh

BMC Cancer 2012 Dec 10;12:585. Epub 2012 Dec 10.

Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.

Background: The clinical implication of Ras/Raf/ERK pathway activity in breast cancer tissue and its association with response to chemotherapy is controversial. We aimed to explore the value of p90RSK phosphorylation, a downstram molecule of the pathway, in predicting chemotherapy response in breast cancer.

Methods: The expression of phosphorylated p90RSK (phospho-p90RSK) and chemotherapy response was measured in 11 breast cancer cell lines and 21 breast cancer tissues. The predictive value of phospho-p90RSK was validated in core needle biopsy specimens of 112 locally advanced breast cancer patients who received anthracycline and taxane-based neoadjuvant chemotherapy.

Results: In 11 breast cancer cell lines, the relative expression of phospho-p90RSK was inversely correlated with cell survival after doxorubicin treatment (p = 0.021). Similar association was observed in fresh tissues from 21 breast cancer patients in terms of clinical response. In paraffin-embedded, formalin-fixed tissues from core needle biopsy tissues from 112 patients, positive phospho-p90RSK expression was associated with greater tumor shrinkage and smaller post-chemotherapy tumor size. The association between phospho-p90RSK expression and chemotherapy response was more evident in estrogen receptor(ER)-positive tumors. The expression of phosphor-p90RSK did not show a significant relationship with the incidence of pCR. P90RSK silencing using siRNA did not affect the cancer cell's response to doxorubicin, and the expression of phospho-p90RSK was highly correlated with other Ras/Raf/ERK pathway activation.

Conclusion: Our results suggest that phospho-p90RSK expression, which reflects the tumor's Ras/Raf/ERK/p90RSK pathway activation can be a potential predictive marker for chemotherapy response in ER-positive breast cancer which needs further independent validation.

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http://dx.doi.org/10.1186/1471-2407-12-585	DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523086	PMC

December 2012

Autoantibody to tumor antigen, alpha 2-HS glycoprotein: a novel biomarker of breast cancer screening and diagnosis.

Authors:

Jae Kyo Yi Jong Wook Chang Wonshik Han Jong Won Lee Eunyoung Ko Dong Hyun Kim Ji-Yeon Bae Jonghan Yu Cheolju Lee Myeong-Hee Yu Dong-Young Noh

Cancer Epidemiol Biomarkers Prev 2009 May;18(5):1357-64

Department of Surgery, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Korea.

We sought to identify a new serum biomarker for breast cancer screening and diagnosis using stepwise proteomic analysis of sera from breast cancer patients to detect the presence of autoantibodies that react with urinary protein. Two-dimensional immunoblotting was done for screening autoimmunogenic tumor antigens in the urine of breast cancer patients. Reactive spots were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Among urinary proteins separated by two-dimensional electrophoresis, 13 spots showed strong reactivity with pooled sera from breast cancer patients or control sera. By mass spectrometry, we identified alpha 2-HS glycoprotein (AHSG) as a tumor antigen. Peripheral blood was obtained from 81 women diagnosed with breast cancer before surgery and 73 female donors without evidence of any malignancy for the individual analysis. In one-dimensional Western blot analysis, AHSG autoantibody was detected in 64 of 81 breast cancer patients (79.1%) and in 7 of 73 controls (9.6%). The sensitivity of this test in breast cancer patients was 79.0%. Our results suggest that AHSG and anti-AHSG autoantibody may be useful serum biomarkers for breast cancer screening and diagnosis.

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http://dx.doi.org/10.1158/1055-9965.EPI-08-0696	DOI Listing

May 2009

Proteomic analysis of breast cancer tissue reveals upregulation of actin-remodeling proteins and its relevance to cancer invasiveness.

Authors:

Dong-Hyun Kim Jinhee Bae Jong Won Lee Seon-Young Kim Yong-Hak Kim Ji-Yeon Bae Jae Kyo Yi Myeong-Hee Yu Dong-Young Noh Cheolju Lee

Proteomics Clin Appl 2009 Jan 20;3(1):30-40. Epub 2008 Nov 20.

Functional Proteomics Center, Korea Institute of Science and Technology, Seoul, Korea.

There is an emerging interest in protein expression profiling with the aim of identifying novel diagnostic markers and therapeutic targets in breast cancer. We analyzed breast cancer tissues by 2-D DIGE using a narrow range IPG strip (pH 5.5-6.7) after the immunodepletion of serum albumin and Ig. Sixty-three protein spots were detected with more than ±1.8-fold differences (p <0.05 for three technical replicates) from a set of tissue samples in which three tumor and three nontumor samples were randomly selected from six breast cancer subjects and pooled separately. Of these, 53 proteins were successfully identified by MS. Among the proteins whose levels were increased, we identified three novel WD-repeat-motif-bearing proteins that have been known to be involved in actin remodeling: Arp2/3 complex subunit 2 (p34-Arc), coronin-1A and WD-repeat protein 1 (Wdr1). Significantly increased amounts of p34-Arc and coronin-1A in breast cancer were also shown by Western blot analysis of matched tumor and nontumor tissue samples (N = 11, p <0.05), and were consistent with the mRNA levels retrieved from publicly available microarray databases. The siRNA knockdown of p34-Arc attenuated the invasion of SK-BR3 breast cancer cells into Matrigel. In contrast, the overexpression of coronin-1A increased this invasive activity. Taken together, the cellular levels of p34-Arc and coronin-1A were linked to cancer development and migration. The data obtained from the present study provides new insight into the management of breast cancer.

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http://dx.doi.org/10.1002/prca.200800167	DOI Listing

January 2009

Identification of circulating endorepellin LG3 fragment: Potential use as a serological biomarker for breast cancer.

Authors:

Jong Wook Chang Un-Beom Kang Dong Hyun Kim Jae Kyo Yi Jong Won Lee Dong-Young Noh Cheolju Lee Myeong-Hee Yu

Proteomics Clin Appl 2008 Jan 11;2(1):23-32. Epub 2007 Dec 11.

Functional Proteomics Center, Korea Institute of Science and Technology, Seoul, Korea.

Comparative proteome analysis was performed on the cultured media of human nontumor and malignant breast cell lines, Hs578Bst and Hs578T, respectively, in search of a serological biomarker(s) for breast cancer. Proteins in the conditioned media were separated by 2-D PAGE and then visualized by silver-staining. Eight proteins changed differentially by more than two-fold were identified by MALDI-TOF/TOF MS. Among the proteins identified, the terminal laminin-like globular (LG3) domain of endorepellin, which was recently reported as an antiangiogenesis factor, was decreased in the cancer cell line. We confirmed the bone morphogenic protein-1 (BMP-1) mediated cleavage site on the N-terminus of endorepellin LG3 fragment. This finding suggests that the LG3 fragment is specifically released by a BMP-1 driven limited proteolytic process. The protein was also detected in plasma by Western blot analysis and selected reaction monitoring (SRM). The plasma level of the endorepellin LG3 fragment was significantly lower in breast cancer patients compared to healthy donors (p = 0.017; n = 12). The LG3 protein concentration in the control plasma was measured at approximately 3.7 pmol/mL compared to 1.8 pmol/mL in plasma from the cancer patients. We suggest that these results support the potential use of the endorepellin LG3 fragment as a new serological biomarker for breast cancer.

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http://dx.doi.org/10.1002/prca.200780049	DOI Listing

January 2008

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