Please use this identifier to cite or link to this item: http://hdl.handle.net/123456789/1250
Title: Alternative splicing of ceramide synthase 2 alters levels of specific ceramides and modulates cancer cell proliferation and migration in Luminal B breast cancer subtype
Authors: Arimbasseri, Gopalakrishnan Aneeshkumar
Deo, S V S
Sharma, Ravi Datta
Bajaj, Avinash
Dasgupta, Ujjaini
Pani, Trishna
Rajput, Kajal
Kar, Animesh
Sharma, Harsh
Basak, Rituparna
Medatwal, Nihal
Saha, Sandhini
Dev, Gagan
Kumar, Sharwan
Gupta, Siddhi
Mukhopadhyay, Arnab
Malakar, Dipankar
Maiti, Tushar Kanti
Issue Date: Feb-2021
Publisher: Springer Nature
Abstract: Global dysregulation of RNA splicing and imbalanced sphingolipid metabolism has emerged as promoters of cancer cell transformation. Here, we present specific signature of alternative splicing (AS) events of sphingolipid genes for each breast cancer subtype from the TCGA-BRCA dataset. We show that ceramide synthase 2 (CERS2) undergoes a unique cassette exon event specifically in Luminal B subtype tumors. We validated this exon 8 skipping event in Luminal B cancer cells compared to normal epithelial cells, and in patient-derived tumor tissues compared to matched normal tissues. Differential AS-based survival analysis shows that this AS event of CERS2 is a poor prognostic factor for Luminal B patients. As Exon 8 corresponds to catalytic Lag1p domain, overexpression of AS transcript of CERS2 in Luminal B cancer cells leads to a reduction in the level of very-long-chain ceramides compared to overexpression of protein-coding (PC) transcript of CERS2. We further demonstrate that this AS event-mediated decrease of very-long-chain ceramides leads to enhanced cancer cell proliferation and migration. Therefore, our results show subtype-specific AS of sphingolipid genes as a regulatory mechanism that deregulates sphingolipids like ceramides in breast tumors, and can be explored further as a suitable therapeutic target.
URI: http://hdl.handle.net/123456789/1250
Appears in Collections:Molecular Genetic, Publications

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