# Project 2: Role of ACER2 in Liver Cancer > **NIH NIH P01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2021 · $198,736 ## Abstract Abstract 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. ## Key facts - **NIH application ID:** 10247634 - **Project number:** 5P01CA097132-18 - **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK - **Principal Investigator:** CUNGUI MAO - **Activity code:** P01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $198,736 - **Award type:** 5 - **Project period:** 2003-08-01 → 2024-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10247634 ## Citation > US National Institutes of Health, RePORTER application 10247634, Project 2: Role of ACER2 in Liver Cancer (5P01CA097132-18). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10247634. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*