Seminar - Madiha Kanwal

Breaking barriers: unraveling the intricate effect of aspartate b-hydroxylase inhibition on cancer cell behavior

Madiha Kanwal

Faculty of Science, Charles University - Laboratory of Immunotherapy

Cancer development involves alterations in key cellular pathways, with the aspartate b-hydroxylase (ASPH) emerging as an important player in tumorigenesis. ASPH promotes cell proliferation, migration, and invasion by modulating the Notch and SRC pathways and has been shown to be upregulated in various cancer types. To unravel its possible other oncogenic mechanisms, we investigated the effect of ASPH on mouse tumor cell lines. Targeting the ASPH catalytic activity using a second-generation small molecule inhibitor MO-I-1151 and silencing ASPH expression via CRISPR/Cas9 significantly reduced the proliferation, migration, and invasiveness of the tumor cell lines. This effect was independent of the Notch or SRC signaling pathways. To explore the molecular mechanisms involved in ASPH-mediated oncogenicity, we then performed transcriptome analysis using bulk RNA sequencing, which revealed Ly6a and Ly6c1 members of the lymphocyte antigen 6 (Ly6) family as potential downstream targets of ASPH signaling, suggesting a novel mechanism of this signaling. Their downregulation was further verified by immunoblotting at the protein level. Inhibition of ASPH also resulted in reduced production of Ly6D and Ly6K members of the Ly6 family in human tumor cell lines.  Since some Ly6 proteins have been found to be associated with cancer progression and poor prognosis, our results suggest that ASPH promotes tumor progression, at least partially, by altering the expression of Ly6 genes.