Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression

Abstract

Tissue-specific alternative splicing is critical for the emergence of tissue identity during development, yet the role of this process in malignant transformation is undefined. Tissue-specific splicing involves evolutionarily conserved, alternative exons that represent only a minority of the total alternative exons identified. Many of these conserved exons have functional features that influence signaling pathways to profound biological effect. Here, we determined that lineage-specific splicing of a brain-enriched cassette exon in the membrane-binding tumor suppressor annexin A7 (ANXA7) diminishes endosomal targeting of the EGFR oncoprotein, consequently enhancing EGFR signaling during brain tumor progression. ANXA7 exon splicing was mediated by the ribonucleoprotein PTBP1, which is normally repressed during neuronal development. PTBP1 was highly expressed in glioblastomas due to loss of a brain-enriched microRNA (miR-124) and to PTBP1 amplification. The alternative ANXA7 splicing trait was present in precursor cells, suggesting that glioblastoma cells inherit the trait from a potential tumor-initiating ancestor and that these cells exploit this trait through accumulation of mutations that enhance EGFR signaling. Our data illustrate that lineage-specific splicing of a tissue-regulated alternative exon in a constituent of an oncogenic pathway eliminates tumor suppressor functions and promotes glioblastoma progression. This paradigm may offer a general model as to how tissue-specific regulatory mechanisms can reprogram normal developmental processes into oncogenic ones.

RNA Splicing Modulation Selectively Impairs Leukemia Stem Cell Maintenance in Secondary Human AML

“…Thus, splicing modulation leading to BCL2 family splice isoform reprogramming may represent a key component of therapeutic strategies aimed at inducing selective clearance of senescent HSC during normal aging, and eradicating therapy-resistant AML LSC. The results of the present study indicate splicing modulation impairs LSC maintenance primarily through reducing LSC self-renewal, which has direct relevance to the treatment of a variety of advanced stage hematopoietic malignancies and cancer stem cell-driven solid tumors (Barrett et al, 2015; DeBoever et al, 2015; Ferrarese et al, 2014; Salton et al, 2015). Additionally, these studies provide the necessary rationale for carrying out pharmacokinetic analyses including in vivo monitoring of 17 S -FD-895 and potential generation of breakdown products, to provide important information on the stability and distribution of this compound compared with less stable spliceosome-targeted small molecules (Hong et al, 2014).…”

MYCN controls an alternative RNA splicing program in high-risk metastatic neuroblastoma

“…Previous studies have showed that repressing PTBP1 expression enhances neuron differentiation [37, 61]. Moreover, PTBP1 is involved in aberrant splicing in glioblastoma and breast cancer [15, 58]. Mutations in HNRNPA1 cause multisystem proteinopathy and ALS [25], and the function of this gene is linked to muscle differentiation and cell survival [22, 62].…”

Uncovering the roles of long noncoding RNAs in neural development and glioma progression

“…Included in this set is the gene neighbor of Pnky, BRN2 , and chromatin-state maps of the Pnky/Brn2 locus in tumor-propagating cells revealed widespread active chromatin marks at the promoters [96]. Further, the protein-binding partner of Pnky , PTBP1 [97], is upregulated in GBM and functions as a driver of tumor growth. The Pnky /PTBP1 complex is therefore an attractive therapeutic target in GBM that was first discovered through careful study of the lncRNAs of the V-SVZ lineage.…”