Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression
27.05.2014
Ferrarese R, Harsh GR 4th, Yadav AK, Bug E, Maticzka D, Reichardt W, Dombrowski SM, Miller TE, Masilamani AP, Dai F, Kim H, Hadler M, Scholtens DM, Yu IL, Beck J, Srinivasasainagendra V, Costa F, Baxan N, Pfeifer D, von Elverfeldt D, Backofen R, Weyerbrock A, Duarte CW, He X, Prinz M, Chandler JP, Vogel H, Chakravarti A, Rich JN, Carro MS, Bredel M.
J Clin Invest. 2014 Jul 1;124(7):2861-76
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. 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. This paradigm may offer a general model as to how tissue-specific regulatory mechanisms can reprogram normal developmental processes into oncogenic ones.
