Hepatocellular carcinoma (HCC), a major type of liver cancer, is a leading cause of cancer deaths worldwide. HCC remains refractory to most treatment options; hence, new therapeutic modalities are urgently needed. Our long-term goal is to develop novel HCC therapeutics based on a deep understanding of its pathogenesis. The specific goal of this application is to define a novel tumor suppressive role for the alkaline ceramidase 2 (ACER2) pathway in HCC development and progression. ACER2 is a member in the alkaline ceramidase family that we identified initially from the yeast Saccharomyces cerevisiae and then from mammals. ACER2 catalyzes the hydrolysis of ceramides to generate sphingosine (SPH), a bioactive lipid implicated in programmed cell death (PCD) and autophagy. We identify ACER2 as a novel transcriptional target of p53 and demonstrate that the ACER2/SPH pathway is a novel signaling axis that operates downstream of p53 to mediate PCD in response to DNA damage. According to the TCGA database, ACER2 is mutated or deleted suppressed in several cancers. A previous study finds that ACER2 is epigenetically repressed in HCC and our preliminary results reveal that ACER2 is downregulated in liver tumors compared to patient-matched adjacent non-tumor liver tissues. Remarkably, we find that mice deficient in the alkaline ceramidase 2 (Acer2) gene are more susceptible to age- related development of various spontaneous tumor types including liver tumors, suggesting that ACER2 is a novel tumor suppressor. According to these exciting findings, we hypothesize that ACER2 is a novel tumor suppressor whose suppression promotes HCC development, progression, and resistance to DNA-damaging chemotherapeutics. As a further corollary, we hypothesize that rectifying the ACER2/SPH pathway will inhibit HCC and overcome the resistance of HCC to chemotherapeutics. These hypotheses will be tested in three interrelated specific aims:
Aim 1 Establish that ACER2 plays a key tumor suppressive role in HCC using a liver carcinogenesis mouse model and liver organoid model, Aim 2 Define the cellular and molecular mechanisms by which the repression of the ACER2/SPH pathway promotes liver tumorigenesis, and Aim 3 Establish the role of the ACER2 pathway in improving the radio/chemotherapy of HCC. Successful completion of these aims will 1) validate the tumor suppressive role of the newly-identified tumor suppressor ACER2; 2) offer novel insights into the mechanisms by which the newly identified p53/ACER2/SPH signaling axis mediates the DNA damage response and tumor suppression; and 3) provide a proof of concept to develop the ACER2/SPH pathway into a novel therapeutic target for HCC. Given the poor clinical outcome of patients with HCC, these studies may have widespread impact on the clinical management of these patients.

Public Health Relevance

Liver cancer is a leading cause of cancer deaths worldwide. Liver cancer remains refractory to many treatment options; hence, new therapeutic modalities are urgently needed. The specific goal of this application is to investigate how the alkaline ceramidase 2 gene (ACER2), a newly identified tumor suppressor gene, suppresses liver cancer development and progression and whether increasing its expression can boost liver cancer chemotherapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
State University New York Stony Brook
Stony Brook
United States
Zip Code
Bai, Aiping; Bielawska, Alicja; Rahmaniyan, Mehrdad et al. (2018) Dose dependent actions of LCL521 on acid ceramidase and key sphingolipid metabolites. Bioorg Med Chem 26:6067-6075
Newcomb, Benjamin; Rhein, Cosima; Mileva, Izolda et al. (2018) Identification of an acid sphingomyelinase ceramide kinase pathway in the regulation of the chemokine CCL5. J Lipid Res 59:1219-1229
Espaillat, Mel Pilar; Snider, Ashley J; Qiu, Zhijuan et al. (2018) Loss of acid ceramidase in myeloid cells suppresses intestinal neutrophil recruitment. FASEB J 32:2339-2353
Hannun, Yusuf A; Obeid, Lina M (2018) Sphingolipids and their metabolism in physiology and disease. Nat Rev Mol Cell Biol 19:175-191
Schwartz, Nicholas U; Linzer, Ryan W; Truman, Jean-Philip et al. (2018) Decreased ceramide underlies mitochondrial dysfunction in Charcot-Marie-Tooth 2F. FASEB J 32:1716-1728
Moorthi, Sitapriya; Burns, Tara Ann; Yu, Gui-Qin et al. (2018) Bcr-Abl regulation of sphingomyelin synthase 1 reveals a novel oncogenic-driven mechanism of protein up-regulation. FASEB J 32:4270-4283
Morris, Thomas G; Borland, Samantha J; Clarke, Christopher J et al. (2018) Sphingosine 1-phosphate activation of ERM contributes to vascular calcification. J Lipid Res 59:69-78
Coant, Nicolas; García-Barros, Mónica; Zhang, Qifeng et al. (2018) AKT as a key target for growth promoting functions of neutral ceramidase in colon cancer cells. Oncogene 37:3852-3863
Ren, Jihui; Snider, Justin; Airola, Michael V et al. (2018) Quantification of 3-ketodihydrosphingosine using HPLC-ESI-MS/MS to study SPT activity in yeast Saccharomyces cerevisiae. J Lipid Res 59:162-170
Shimizu, Yoshiko; Furuya, Hideki; Tamashiro, Paulette M et al. (2018) Genetic deletion of sphingosine kinase 1 suppresses mouse breast tumor development in an HER2 transgenic model. Carcinogenesis 39:47-55

Showing the most recent 10 out of 215 publications