Aspartate-β-Hydroxylase: A Promising Target to Limit the Local Invasiveness of Colorectal Cancer

Abstract

Colorectal cancer’s (CRC) ability to invade local tissues and lymph nodes and generate distant metastases is the key for TNM classification. Aspartate-β-hydroxylase (ASPH), a transmembrane protein that catalyzes Notch receptors and ligand activation, is involved in tumor invasion. Because Notch is involved in gut homeostasis, it could be a target for CRC therapy. ASPH mRNA and protein expression, promoter methylation and gene copy numbers were evaluated using the TCGA and CPTAC human CRC datasets. Using digital pathology, ASPH was scored in the luminal area (LM), center tumor (CT) and invasive margin (IM) of 100 human CRCs. The effect of ASPH targeting on invasiveness and viability was tested by siRNA knockdown and small molecule inhibitors (SMI). Bioinformatics analysis showed increased expression of ASPH mRNA and protein in CRC, paired with a decreased methylation profile. ASPH genetic gain or amplification was frequent (56%), while deletion was rare (0.03%). Digital pathology analysis showed that ASPH exerted its pathological activity in the invasive margin of the tumor, affecting invasive front morphology, tumor budding and patients’ overall survival. In vitro, ASPH targeting by siRNA or SMI reduced cell invasion and growth and caused Notch-1 downregulation. This study demonstrates that ASPH targeting by specific inhibitors could improve CRC treatment strategies.

Aspartate β-hydroxylase as a target for cancer therapy

“…In the study by Kadota et al [55], the ASPH gene locus has been identified as one of the DNA regions with focal amplification in primary breast cancer. In colorectal cancer, ASPH gain or amplification was found in 56% of samples [56]. Next, a suppressant role of the microRNA miR-200a in posttranscription regulation of the ASPH expression in hepatoma cells has been found [57].…”

“…Oncogenic abilities of ASPH have been experimentally demonstrated using tumor cell lines and mouse and rat models of different types of human tumors with ASPH overexpression, including cholangiocarcinoma [ 4 , 44 , 75 , 87 , 88 ], hepatocellular carcinoma [ 5 , 37 , 38 , 57 , 62 , 70 , 73 ], neuroblastoma [ 30 ], pancreatic cancer [ 7 , 41 , 43 , 71 ], glioma [ 6 ], breast carcinoma [ 42 ], castration-resistant prostate cancer [ 66 ], and colorectal cancer [ 56 ]. In studies analyzing ASPH function, various approaches were utilized to reveal signaling pathways affected by ASPH.…”

Diverse molecular functions of aspartate β‑hydroxylase in cancer (Review)

“…CRC is the fourth most deadly cancer, with ~900,000 deaths annually worldwide in 2019 ( 80 ). A bioinformatics analysis revealed that the mRNA and protein levels of AspH are upregulated in CRC compared with in normal tissues due to gene copy number variations and promoter demethylation ( 81 ). AspH accumulates at the invasive tumor margin, which may be associated with cell invasion and infiltration ( 81 ).…”

“…A bioinformatics analysis revealed that the mRNA and protein levels of AspH are upregulated in CRC compared with in normal tissues due to gene copy number variations and promoter demethylation ( 81 ). AspH accumulates at the invasive tumor margin, which may be associated with cell invasion and infiltration ( 81 ). It has been recently reported that Notch signaling recruits TGFβ-dependent neutrophils to drive CRC metastasis; this pathway has an important role in the tumor microenvironment and predicts a poor survival in patients with CRC ( 82 ).…”

“…It has been recently reported that Notch signaling recruits TGFβ-dependent neutrophils to drive CRC metastasis; this pathway has an important role in the tumor microenvironment and predicts a poor survival in patients with CRC ( 82 ). Notably, knocking down AspH or using specific SMIs (MO-I-1144) decreases Notch expression in CRC, inhibiting tumor development and metastasis ( 81 ).…”