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Regulation of EMT-MET and chemoresistance by the Lc3Cer-synthase B3GNT5
Laura E Clark1, Katherine Hylton Rorie1, Amanda J G Dickinson1
1Department of Biology, Virginia Commonwealth University, Richmond, VA, 23284, USA.
Background:
Glycosphingolipids (GSL) are essential components of the plasma membrane where they are known to play key structural and functional roles and are known to influence molecular processes involved in cancer malignancy, including multi-drug chemoresistance, the epithelial to mesenchymal transition (EMT), and the activation or receptor tyrosine kinases (RTK). Thus, investigating and understanding how GSLs are regulated in cancer and the impact they have on malignancy have important therapeutic potential. In the GSL biosynthetic pathway, one critical regulator of two of the four major branches of GSLs is the gene product of B3GNT5, which produces the precursor for all GSLs in the lactoside and neolactoside series.
Methods:
Publicly available data was mined to determine the types and prevalence of genetic lesions at the B3GNT5 locus in various cancers, and to assess the impact of increased expression on patient outcomes. HeLa cells in which B3GNT5 was partially depleted using CRISPR-Cas9 approaches were used to determine how its expression levels impacted several phenotypic properties associated with cancer malignancy. Mass spectrometry was used to assess the effect of B3GNT5 on the levels of the Lc3Cer precursors glucosylceramide (GlcCer) and lactosylceramide (LacCer).
Results:
B3GNT5 copy number gain and overexpression are widespread across human cancers and are significantly associated with poor prognosis. Partial depletion of B3GNT5 in HeLa cells led to accumulation of GlcCer and LacCer, increased chemoresistance, altered EMT marker expression, and decreased activation of multiple RTKs following stimulation with serum-suggesting broad signaling and phenotypic shifts.
Conclusions:
B3GNT5 is frequently altered in human cancers and correlates with adverse clinical outcomes. Functional depletion reveals its key role in regulating glycosphingolipid metabolism, signaling, and malignant phenotypes. These findings support B3GNT5 as an important target for therapeutic intervention in cancer.
Insights
The gene B3GNT5 regulates glycosphingolipids (GSLs) crucial for cancer malignancy. Its alteration in cancers correlates with poor outcomes, suggesting B3GNT5 as a potential therapeutic target.
Area of Science:
- Biochemistry
- Cancer Biology
- Molecular Oncology
Background:
- Glycosphingolipids (GSLs) are vital plasma membrane components influencing cancer malignancy, including chemoresistance, epithelial-mesenchymal transition (EMT), and receptor tyrosine kinase (RTK) activation.
- B3GNT5 is a key regulator in GSL biosynthesis, producing precursors for lactoside and neolactoside GSL series.
Purpose of the Study:
- To investigate the role of B3GNT5 in cancer malignancy.
- To assess the impact of B3GNT5 alterations and expression on cancer progression and patient outcomes.
Main Methods:
- Analysis of publicly available cancer genomic data for B3GNT5 lesions and expression.
- CRISPR-Cas9 mediated partial depletion of B3GNT5 in HeLa cells to assess phenotypic changes.
- Mass spectrometry to quantify GSL precursors (GlcCer, LacCer) affected by B3GNT5 levels.
Main Results:
- B3GNT5 copy number gains and overexpression are prevalent in human cancers, correlating with poor prognosis.
- Partial B3GNT5 depletion in HeLa cells resulted in GlcCer and LacCer accumulation, increased chemoresistance, altered EMT markers, and reduced RTK activation.
- These findings indicate B3GNT5 influences GSL metabolism, signaling pathways, and malignant phenotypes.
Conclusions:
- B3GNT5 alterations are frequent in cancer and linked to adverse outcomes.
- B3GNT5 plays a critical role in GSL metabolism, cancer signaling, and malignant phenotypes.
- B3GNT5 represents a promising therapeutic target for cancer treatment.
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