p73 promotes glioblastoma cell invasion by directly activating POSTN (periostin) expression

Abstract

Glioblastoma Multiforme is one of the most highly metastatic cancers and constitutes 70% of all gliomas. Despite aggressive treatments these tumours have an exceptionally bad prognosis, mainly due to therapy resistance and tumour recurrence. Here we show that the transcription factor p73 confers an invasive phenotype by directly activating expression of POSTN (periostin, HGNC:16953) in glioblastoma cells. Knock down of endogenous p73 reduces invasiveness and chemo-resistance, and promotes differentiation in vitro. Using chromatin immunoprecipitation and reporter assays we demonstrate that POSTN, an integrin binding protein that has recently been shown to play a major role in metastasis, is a transcriptional target of TAp73. We further show that POSTN overexpression is sufficient to rescue the invasive phenotype of glioblastoma cells after p73 knock down. Additionally, bioinformatics analysis revealed that an intact p73/POSTN axis, where POSTN and p73 expression is correlated, predicts bad prognosis in several cancer types. Taken together, our results support a novel role of TAp73 in controlling glioblastoma cell invasion by regulating the expression of the matricellular protein POSTN.

Integrin-β4 is a novel transcriptional target of TAp73

“…p53 family can be considered among the most powerful family of genes for the wide range of functions covering from tumour suppression, homeostasis and development [1][2][3][4][5][6][7][8][9][10][11]. In this context the p53 family member p73 plays critical roles such as tumour suppression [12][13][14][15][16][17], neuronal development and differentiation [18][19][20][21][22][23][24], metabolic control [25][26][27][28][29][30][31][32][33], and spermatogenesis and the maintenance of male and female fertility [34][35][36][37]. However, despite the important effort placed in investigating p73 functioning, a full dissections of its transcriptional programme and a clearly distinction of this from the transcriptome of its sibling p53 has not been completely elucidated.…”

Cross-species transcriptional analysis reveals conserved and host-specific neoplastic processes in mammalian glioma

“…In order to validate these transcriptional observations, the expression pattern of several of the corresponding protein products was assessed by IF microscopy. The DEGs examined included (1) TNFRSF12A (Fn14), which encodes a cell surface protein that binds the ligand TWEAK and is over-expressed in many human solid tumor types including GBM 31 , 32 ; (2) BMP-7, which encodes a member of the TGF-β superfamily implicated in glioma cell growth control and stem-like glioma cell properties 33 – 35 ; and (3) POSTN, which encodes a secreted matricellular protein overexpressed in GBM that binds integrins and plays a role in macrophage recruitment and glioma cell invasion 36 – 38 . In agreement with the mRNA expression analysis data, TNFRSF12A expression was not detected in canine tumor tissue (Supplementary Figure 2C ), BMP-7 expression was not detected in rat tumor tissue (Supplementary Figure 2D ), and POSTN expression was not detected in mouse tumor tissue (Supplementary Figure 2E ).…”

p53-Related Transcription Targets of TAp73 in Cancer Cells—Bona Fide or Distorted Reality?

“…In contrast to individual studies that identified and validated one or a few genes, high-throughput techniques such as microarray and Next-Generation Sequencing have also been used to identify TAp73 target genes across the entire genome, mostly focusing on coding genes. Based on our search term and analysis criteria, 12 articles published between 2008 and 2018 reported genome-wide studies aimed at identifying genes regulated by TAp73 in cancer cells [42,45,91,103,[112][113][114][115][116][117][118][119]. These studies utilized various techniques such as microarray (six studies), RNA-Seq (one study), ChIP-on-ChIP (three studies), and ChIP-Seq (three studies).…”

“…CDKN1A is a major target of p53 that induces cell cycle arrest upon DNA damage [123]. On the other hand, POSTN that codes for Periostin, activates the Akt-and FAK-mediated signaling pathways to promote cancer cell motility and the epithelial-mesenchymal transition [103]. Table 4.…”