RNA‐binding protein RBM24 represses colorectal tumourigenesis by stabilising PTEN mRNA

Abstract

Background RNA‐binding motif protein 24 (RBM24) functions as a splicing regulator, which is critical for organ development and is dysregulated in human cancers. Here, we aim to uncover the biological function of RBM24 in colorectal tumourigenesis. Methods Xenograft tumour model, Rbm24 knockout and Apc min/+ mouse models were utilised. Colorectal cancer cells overexpressing or silencing RBM24 were established. RNA immunoprecipitation (RIP) assay was conducted to detect protein‐RNA associations. Gene expression was measured by immunohistochemistry, western blotting, or quantitative PCR (qPCR). Results Rbm24‐knockout mice developed spontaneous colorectal adenomas with lower expression of phosphatase and tensin homolog (PTEN). Immunohistochemical staining for the proliferation markers Ki‐67 and pHH3 and BrdU assay showed intestinal hyperplasia in Rbm24‐knockout mice compared to wild‐type mice. RBM24 expression in colorectal adenoma tissues of Apc min/+ mouse was downregulated compared with adjacent normal samples and was positively correlated with PTEN expression. In vitro, RBM24 overexpression suppressed cell proliferation, migration, invasion and increased sensitivity to 5‐FU or cisplatin in CRC cells. Mechanistically, RBM24 maintained PTEN mRNA stability by directly binding to the GT‐rich region at positions 8101–8251 in the 3′‐UTR of PTEN mRNA, prolonging the half‐life of PTEN mRNA, thereby increasing PTEN expression. Hence, low expression of RBM24 downregulated PTEN mRNA, causing the activation of PI3K‐Akt signalling in CRC cells. Furthermore, RBM24 expression in CRC tissues was lower than adjacent normal samples. RBM24 expression was positively correlated with PTEN expression and negatively correlated with Ki‐67 level. CRC patients with high RBM24 expression had a favourable outcome. Conclusions Taken together, RBM24 expression is markedly lower in colorectal tumours than in para‐carcinoma tissues. Rbm24‐knockout mice develop spontaneous colorectal adenomas. RBM24 directly binds and stabilises PTEN mRNA, which could cause the suppression of CRC cell proliferation, migration and invasion, thereby repressing colorectal tumourigenesis. These findings support the tumour‐suppressive role of RBM24. Targeting RBM24 holds strong promise for the diagnosis and treatment of CRC.

Alternative splicing downstream of EMT enhances phenotypic plasticity and malignant behavior in colon cancer

“…The increased expression of other RBP-coding genes such as RBM24 and MBNL2 (muscleblind-like 2) in CMS4 tumors and in EpCAM lo cells is also in sharp contradiction with their alleged tumor suppressing roles in colon and other cancers 45, 46 . Of note, MBNL2 regulates cancer migration and invasion through PI3K/AKT-mediated EMT 46 and its overexpression in breast and cancer cell lines inhibits their metastatic potential 47 .…”

RBM24 in the Post-Transcriptional Regulation of Cancer Progression: Anti-Tumor or Pro-Tumor Activity?

“…Thus, the outcome of RBM24-regulated p63 mRNA stability on the expression TAp63 and ΔNp63 isoforms as well as the consequence on tumor development merit further investigation. Recent studies show that by binding to the 3′-UTR, RBM24 stabilizes RUNX1T1 (RUNX1-related transcription factor 1) mRNA in bladder carcinoma and PTEN (phosphatase and tensin homolog) mRNA in colorectal cancer (CRC), with opposite effects on tumor progression [ 32 , 36 ].…”

“…Evidence is accumulating that RBM24 plays an important role in gastrointestinal cancers through different post-transcriptional mechanisms. One study demonstrates that RBM24 expression is strongly downregulated in colorectal tumor tissues from human patients and that spontaneous colorectal adenomas appear in RBM24 -knockout mice [ 32 ]. This suggests that RBM24 has potential tumor suppressor function.…”

“…Consistently, overexpression of RBM24 can inhibit metastasis of CRC cells and xenografts. Mechanistically, RBM24 promotes the accumulation of PTEN protein, a tumor suppressor and a negative regulator of PI3K (phosphoinositide 3-kinase) signaling, by directly binding to the 3′-UTR and increasing the stability of PTEN mRNA [ 32 ]. These results show that RBM24 can repress CRC progression by promoting the expression of tumor suppressor proteins.…”

“…Functional and correlative analyses suggest that it displays either anti-oncogenic or oncogenic potential. Several studies suggest that it suppresses tumor progression [ 28 , 29 , 30 , 31 , 32 ], while others indicate that its upregulation promotes tumor growth [ 33 , 34 , 35 , 36 , 37 ]. These raise the possibility that RBM24 may act either as a tumor suppressor or as an oncogene, functioning in a context- or background-dependent manner.…”