Splicing Regulators and Their Roles in Cancer Biology and Therapy

Abstract

Alternative splicing allows cells to expand the encoding potential of their genomes. In this elegant mechanism, a single gene can yield protein isoforms with even antagonistic functions depending on the cellular physiological context. Alterations in splicing regulatory factors activity in cancer cells, however, can generate an abnormal protein expression pattern that promotes growth, survival, and other processes, which are relevant to tumor biology. In this review, we discuss dysregulated alternative splicing events and regulatory factors that impact pathways related to cancer. The SR proteins and their regulatory kinases SRPKs and CLKs have been frequently found altered in tumors and are examined in more detail. Finally, perspectives that support splicing machinery as target for the development of novel anticancer therapies are discussed.

Effects of Thymoquinone on IL-6 Gene Expression and Some Cellular Signaling Pathways in Prostate Cancer PC3 Cells

“…TQ can prevent proliferation and angiogenesis by suppressing ERK and AKT phosphorylation in human umbilical vein endothelial cells (HUVECs). The current study findings demonstrated that pERK1/2 signaling pathways were diminished by TQ (Figure 3), which was in line with previously published papers (34,35,38). Thus, additional mechanism for antiproliferative effects of TQ on PC3 cells may be applied by inhibiting pERK1/2 signaling pathway.…”

“…On the other hand, AKT is implicated in the progression of many human cancers, because it controls several factors involved in the apoptosis and cell cycle progression (33), which is in agreement with the findings of the current study. Also, ERK is a key regulatory kinase to control endothelial cell cycle, proliferation, growth, migration, and apoptosis in various types of cancers (34,35). Therefore in the current study, another possible mechanism for antiproliferative effects of TQ on PC3 cells, at least in part, can be applied by reducing pAKT signaling pathway.…”

The Oxidative Stress Pathway May be an Important Pathway Leading to The Recurrence of Ewing Sarcoma —— Based On Weighted Gene Co-Expression Network Analysis

“…At present, it has been found that there are a large number of RS domain proteins in organisms, among which about 50 species of higher organisms participate in RNA splicing [16]. The splicing factor activity of this family is regulated by reversible phosphorylation mediated by protein kinases belonging to SRPK and CLK families and by kinases activated by different signaling pathways such as MAPK, PI3K and Akt [17]. They are involved in tumor apoptosis by activating ROS and other oxidative stress pathways through interaction, and affect recurrence and metastasis [18].…”

Influence of transcriptional variants on metastasis

“…In summary, the major genomic and transcriptomic changes are as follows: (i) the presence of mutations in transcription factor binding and splice sites; (ii) mutations that generates aberrant proteins; (iii) different DNA arrangements and histone modifications; (iv) changes in chromatin accessibility; and (v) altered expression of splicing factors and transcription factors [6]. In the past, drugs that act on specific cellular targets were used without regard for the aberrant isoforms generated during oncogenesis, mostly due to missing information regarding the isoform variants in a gene [6,166]. The differential expression of several isoforms encoded by the same gene might be a contributing factor to the observed variation in patient responses during drug treatment [6,166].…”