Abstract
The multifunctional protein, splicing factor, proline- and glutamine-rich (SFPQ) has been implicated in numerous cancers often due to interaction with coding and non-coding RNAs, however, its role in melanoma remains unclear. We report that knockdown of SFPQ expression in melanoma cells decelerates several cancer-associated cell phenotypes, including cell growth, migration, epithelial to mesenchymal transition, apoptosis, and glycolysis. RIP-seq analysis revealed that the SFPQ-RNA interactome is reprogrammed in melanoma cells and specifically enriched with key melanoma-associated coding and long non-coding transcripts, including SOX10, AMIGO2 and LINC00511 and in most cases SFPQ is required for the efficient expression of these genes. Functional analysis of two SFPQ-enriched lncRNA, LINC00511 and LINC01234, demonstrated that these genes independently contribute to the melanoma phenotype and a more detailed analysis of LINC00511 indicated that this occurs in part via modulation of the miR-625-5p/PKM2 axis. Importantly, analysis of a large clinical cohort revealed that elevated expression of SFPQ in primary melanoma tumours may have utility as a prognostic biomarker. Together, these data suggest that SFPQ is an important driver of melanoma, likely due to SFPQ–RNA interactions promoting the expression of numerous oncogenic transcripts.
Highlights
At the molecular level, melanoma comprises a heterogeneous group of disorders that harbour distinct aberrations in diverse cellular processes [1,2,3]
SFPQ has been identified as an essential melanoma gene in a CRISPR genomewide loss of function screen [26], and analysis of this dataset revealed that melanoma cell lines (n = 46) show high dependency (DEMETER2 scores) on SFPQ regardless of its expression
We explored if SFPQ expression was required for ‘cancer cell phenotypes’, in vitro, including increased cell growth, cell migration, epithelial to mesenchymal transition (EMT) and decreased apoptosis and oxidative phosphorylation (OXPHOS)
Summary
Melanoma comprises a heterogeneous group of disorders that harbour distinct aberrations in diverse cellular processes [1,2,3] Such heterogeneity suggests that multiple mechanisms are involved in disease aetiology, and this is reflected in the contribution of both different mutations and differential gene and protein expression associated with melanoma transformation and progression [4]. Aberrant SFPQ function is associated with the aetiology of neurodegenerative disorders [10,11,12] and colorectal [13], hepatocellular [14], renal [15], Chronic Myeloid Leukaemia [16] and prostate cancer [17] It appears that SFPQ-long non-coding RNA (lncRNA) interactions are responsible for pathological changes in numerous cancers [14, 15, 18] including breast [19, 20] and ovarian tumours [21]. Dysregulated expression of lncRNA has been shown to correlate with poor outcome across a range on neoplasms, with increasing numbers of lncRNA being implicated in driving metastasis [23,24,25]
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