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  3. Targeting SRPK1 to regulate alternative splicing in prostate cancer: the roles of MALAT1 and TUG1

Targeting SRPK1 to regulate alternative splicing in prostate cancer: the roles of MALAT1 and TUG1

  • Mol Biol Rep. 2025 Nov 6;53(1):55. doi: 10.1007/s11033-025-11185-9.
Linomtha Gabada 1 2,  Afra Basera 1,  Babatunde Adebola Alabi 1,  Zodwa Dlamini 1,  Rahaba Marima 3
Affiliations

Affiliations

  • 1 SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision, Oncology and Cancer Prevention, Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield, 0028, Pretoria, South Africa.
  • 2 Department of Medical Oncology, Steve Biko Academic Hospital, University of Pretoria, Hatfield, 0028, Pretoria, South Africa.
  • 3 SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision, Oncology and Cancer Prevention, Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield, 0028, Pretoria, South Africa. [email protected].
PMID: 41196435 DOI: 10.1007/s11033-025-11185-9
Abstract

Background: Prostate Cancer (PCa) is a leading cause of cancer-related mortality, with significant racial disparities in outcomes. Long non-coding RNAs (lncRNAs) MALAT1 and TUG1 are implicated in oncogenic pathways. Aberrant RNA splicing, a hallmark of Cancer, is often driven by dysregulation of serine-arginine protein kinase 1 (SRPK1), a key spliceosome regulator. The relationship between lncRNAs of splicing factors in Cancer pathways remains underexplored, and thus, this study aimed to elucidate the roles of MALAT1 and TUG1 lncRNAs in relation to the SRPK1 inhibitor SPHINX31 in PCa.

Methods: Bioinformatics tools were used to analyze interactions between` MALAT1, TUG1, relevant miRNAs, and target genes. A resazurin assay assessed PCa cell viability (PC-3 vs. HEK293) in response to SPHINX31 at 24 and 48 h. RT-qPCR was used to quantify MALAT1 and TUG1 lncRNAs expression levels.

Results: The Alamar Blue assay indicated a time-dependent reduction in PC3 cell viability with 3 µM SPHINX31, particularly at 48 h. RT-qPCR revealed significant regulation of MALAT1 and TUG1, highlighting SRPK1's role in RNA pathways critical for tumor survival. SPHINX31 induced similar cytotoxic effects in HEK293 cells, illustrating the need for selective tumor specificity. MALAT1 expression was upregulated at 24 h, followed by a decline at 48 h, indicating cumulative cellular stress in PC-3 cells.

Discussion: This study demonstrated that SRPK1 inhibition alters lncRNA expression and splicing-related events in PCa. These findings highlight SPHINX31's potential as a therapeutic agent, especially in combination with treatments like Olaparib, necessitating further optimization for selectivity and reduced off-target effects.

Keywords

Alternative splicing; Angiogenesis; CeRNAs; Long non-coding RNAs; MALAT1; Prostate cancer; SRPK1; TUG1.

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