The p53-induced RNA-binding protein ZMAT3 is a splicing regulator that inhibits the splicing of oncogenic CD44 variants in colorectal carcinoma

Abstract

p53 is an intensely studied tumor-suppressive transcription factor. Recent studies suggest that the RNA-binding protein (RBP) ZMAT3 is important in mediating the tumor-suppressive effects of p53. Here, we globally identify ZMAT3-regulated RNAs and their binding sites at nucleotide resolution in intact colorectal cancer (CRC) cells. ZMAT3 binds to thousands of mRNA precursors, mainly at intronic uridine-rich sequences and affects their splicing. The strongest alternatively spliced ZMAT3 target was CD44, a cell adhesion gene and stem cell marker that controls tumorigenesis. Silencing ZMAT3 increased inclusion of CD44 variant exons, resulting in significant upregulation of oncogenic CD44 isoforms (CD44v) and increased CRC cell growth that was rescued by concurrent knockdown of CD44v. Silencing p53 phenocopied the loss of ZMAT3 with respect to CD44 alternative splicing, suggesting that ZMAT3-mediated regulation of CD44 splicing is vital for p53 function. Collectively, our findings uncover a p53-ZMAT3-CD44 axis in growth suppression in CRC cells.

ZMAT3 hypomethylation contributes to early senescence of preadipocytes from healthy first‐degree relatives of type 2 diabetics

“…Previous investigators showed that, in cancer cell lines, ZMAT3 induced p21 mRNA decay with no change in p53 and suggested that these events cause premature senescence upon ZMAT3 depletion (Kim et al, 2012). However and consistent with our findings, other investigators also showed that ZMAT3 and p21 expression is induced with similar kinetics in both normal and cancer cells (Hellborg et al, 2001; Muys et al, 2020; Parikh et al, 2014), indicating that the effects of ZMAT3 may depend on the cellular context. Based on the evidence presented in this work, we propose that the epigenetic dysregulation of ZMAT3 induces premature senescence in APC of FDR by activating the p53/p21 pathway.…”

p53 and Tumor Suppression: It Takes a Network

“…Combined CLIP-seq and RNA-seq analyses revealed that Zmat3 regulates an alternative splicing program by binding RNAs upstream of 3′ splice sites of specific introns and regulating exon skipping, leading to changes in the transcriptome. These findings, along with a recent study that found that ZMAT3 inhibits clonogenicity of colon cancer cells by controlling the splicing of CD44, suggest a link between p53-mediated tumor suppression and splicing [7,8]. Zmat3 deficiency did not promote tumor growth to the extent of p53 loss, suggesting that Zmat3 is one of multiple tumor suppression effectors downstream of p53.…”

Advances in the study of RNA-binding proteins in diabetic complications

“…There are many relevant regulators, each with different functions under specific conditions [ 43 ]. A study found that Zinc finger Matrin-Type 3 makes oncogenic CD44 variants splicing be inhibited in colorectal carcinoma [ 44 ]. T1D is caused by autoimmune-mediated destruction of pancreatic β cells that produce insulin [ 45 ].…”