Transcription Factors in Cancer: When Alternative Splicing Determines Opposite Cell Fates

Abstract

Alternative splicing (AS) is a finely regulated mechanism for transcriptome and proteome diversification in eukaryotic cells. Correct balance between AS isoforms takes part in molecular mechanisms that properly define spatiotemporal and tissue specific transcriptional programs in physiological conditions. However, several diseases are associated to or even caused by AS alterations. In particular, multiple AS changes occur in cancer cells and sustain the oncogenic transcriptional program. Transcription factors (TFs) represent a key class of proteins that control gene expression by direct binding to DNA regulatory elements. AS events can generate cancer-associated TF isoforms with altered activity, leading to sustained proliferative signaling, differentiation block and apoptosis resistance, all well-known hallmarks of cancer. In this review, we focus on how AS can produce TFs isoforms with opposite transcriptional activities or antagonistic functions that severely impact on cancer biology. This summary points the attention to the relevance of the analysis of TFs splice variants in cancer, which can allow patients stratification despite the presence of interindividual genetic heterogeneity. Recurrent TFs variants that give advantage to specific cancer types not only open the opportunity to use AS transcripts as clinical biomarkers but also guide the development of new anti-cancer strategies in personalized medicine.

Keywords: alternative splicing; cancer; cell death; cell differentiation; cell proliferation; transcription factors.

Figure 1

Possible activity of transcription factor (TF) alternative splicing (AS) isoforms in normal vs. cancer cells. The TF variant expressed in cancer cells (red ASTF) can bind and transcriptionally regulate different set of genes compared to the TF physiologically expressed in normal cells (orange TF). Gene A and gene B represent two different targets of TF isoforms.

Figure 2

TF isoforms expressed in cancer cells (red ASTF) can (a) oppositely control the expression of the same target gene compared to the physiological TF variant (orange TF) through the recruitment of different co-regulators (green CoR) or (b) have reduced affinity for the target gene.

Figure 3

AS isoform of a TF can be mislocalized within cancer cell and exert a dominant negative (DN) activity as the consequence of (a) excessive expression of the non functional isoform (blue DN) compared to the functional one (orange TF) or (b) cytoplasmic titration of the functional TF variant.

Figure 4

TF isoforms can lose the DBD or other domains required for DNA binding of the canonical TF (orange TF), consequently acting as DNs (blue DN).

Figure 5

TF isoforms acting as DNs (blue DN) can preserve DNA binding to target genes but do not have transactivation or repressive potential because of (a) the loss of the TAD or repressive domain (RD) by AS or (b) impaired recruitment of transcriptional co-regulators (green CoR) necessary for proper transcriptional regulation.

Figure 6

The balance between cellular processes that enhance or inhibit cancer hallmarks is controlled by TFs. Specific splice variants that promote (purple boxes) or hamper (orange boxes) neoplastic transformation are reported.