Splicing regulatory factors in breast cancer hallmarks and disease progression

Abstract

By regulating transcript isoform expression levels, alternative splicing provides an additional layer of protein control. Recent studies show evidence that cancer cells use different splicing events to fulfill their requirements in order to develop, progress and metastasize. However, there has been less attention for the role of the complex catalyzing the complicated multistep splicing reaction: the spliceosome. The spliceosome consists of multiple sub-complexes in total comprising 244 proteins or splice factors and 5 associated RNA molecules. Here we discuss the role of splice factors in the oncogenic processes tumors cells need to fulfill their oncogenic properties (the so-called the hallmarks of cancer). Despite the fact that splice factors have been investigated only recently, they seem to play a prominent role in already five hallmarks of cancer: angiogenesis, resisting cell death, sustaining proliferation, deregulating cellular energetics and invasion and metastasis formation by affecting major signaling pathways such as epithelial-to-mesenchymal transition, the Warburg effect, DNA damage response and hormone receptor dependent proliferation. Moreover, we could relate expression of representative genes of four other hallmarks (enabling replicative mortality, genomic instability, avoiding immune destruction and evading growth suppression) to splice factor levels in human breast cancer tumors, suggesting that also these hallmarks could be regulated by splice factors. Since many splice factors are involved in multiple hallmarks of cancer, inhibiting splice factors might provide a new layer of oncogenic control and a powerful method to combat breast cancer progression.

Convergent mutations in tissue-specific regulatory regions reveal novel cancer drivers

“…Further, we identify a IPO9 , a nuclear actin transporter, implicated in mRNA metabolism and alternative splicing, as a putative oncogene in breast cancer, melanoma, bladder cancer, and mesothelioma. In addition to IPO9 , other newly identified regulatory driver genes, including SRSF2 and TCERG1 , also modulate alternative splicing (Koedoot et al, 2019;Montes et al, 2015;Pearson et al, 2008) , suggesting a shared functional basis for these enrichments, similar to that also seen for alternative splicing in coding mutations (Watson et al, 2013) .…”

“…In addition, nuclear actin dynamics, mediated by IPO9 and XPO6 , have the potential to modulate mRNA splicing through disruption of SMN2 (Viita et al, 2019) . Alternative splicing and other co-transcriptional metabolic processes acting on RNA are important for cancer development (David and Manley, 2010;Koedoot et al, 2019) , suggesting a multitude of direct targets in promoting the hallmarks of cancer (Hanahan and Weinberg, 2011) . These diverse roles of nuclear actin in cellular proliferation and transcription are consistent with our findings of mutational enrichment in IPO9 regulatory regions and the association between elevated expression of IPO9 and shorter relapse-free and overall survival in multiple cancer types.…”

Protein co-expression networks identified from HOT lesions of ER+HER2–Ki-67high luminal breast carcinomas

“…Genome-wide association studies analyzing 4,398 cases with familial breast cancer causes and 4,316 controls identified five single-nucleotide polymorphisms of FGFR2 significantly associated with breast cancer 36 . SRPK1 is a serine/arginine-rich protein-specific kinase and one of the core splicing factors 37 ; it is highly expressed in more aggressive basal breast cancer. High expression levels of SRPK1 correlated with low metastasis-free survival in patients with ER-positive, but not ER-negative, breast cancer 38 .…”

PRKCSH Alternative Splicing Involves in Silica-Induced Expression of Epithelial–Mesenchymal Transition Markers and Cell Proliferation

“…(1) As the AS is a critical component of the regulation of gene expression pathways, how the detailed mechanisms and regulation of alternative pre-mRNA splicing should be elucidated. (2) Since many splice factors are involved in multiple hallmarks of diseases, 46 investigation on these factors might provide a new layer of disease treatment or a potential method to combat disease progression. (3) Why different transcripts perform different functions?…”