[Source: reprinted from the Web ]
On March 19, 2024, Qi Xie of West Lake University, Lei Li of the Shenzhen Bay Laboratory and Jeremy N. Rich of the University of Pittsburgh jointly published in Cell Discovery entitled "RBBP6 maintains glioblastoma stem cells through CPSF3-dependent. The alternative polyadenylation "research paper. The study was carried out in parallel in vitro and in vivo CRISPR/Cas9 knockout screening, for human ubiquitin E3 ligase and to ubiquitin enzyme, reveals the E3 ligase RBBP6 GSC as glioblastoma stem cells maintain a necessary factor, targeted RBBP6 inhibits GSC proliferation and tumor initiation.
Ubiquitination is an important post-translational modification, which is involved in the regulation of the occurrence, development, metastasis and recurrence of tumors. It is a potential target for tumor treatment. In this study, a CRISPR-Cas9 library targeting deubiquitinating enzymes and ubiquitin ligases was constructed. To overcome the great difference between in vitro single cell culture conditions and in vivo, a combination of in vivo and in vitro CRISPR-Cas9 screening strategy was used, and ubiquitin ligase RBBP6 was found to be a key molecule in the regulation of GSC.
To clarify the molecular pathway of RBBP6 in regulating GSC, the researchers found that RBBP6 regulated MYC signaling pathway and MYC expression by RNA-seq. Further studies showed that RBBP6 regulated the variable polyadenylation of mRNA, and knockdown of RBBP6 reduced the 3’UTR of MYC competing endogenous RNA (ceRNA) without affecting the length of MYC 3’UTR, releasing free miRNA to inhibit MYC expression, thereby inhibiting the growth of glioblastoma.
To clarify RBBP6 control variable poly a molecular mechanism, through precipitation coupling mass spectrometry analysis found that RBBP6 with variable of adenosine acidification polymer modified regulation factor CPSF3 interactions, mediates its K63 of ubiquitin polymer modification and stabilize its protein levels. To explore targeted RBBP6 / CPSF3 - APA - the possibility of treating GBM MYC axis, the author studies have found that knockout RBBP6 or CPSF3 can significantly inhibit tumor growth in mouse models of GBM, prolong survival tumor-burdened mice. Since there is no RBBP6 inhibitor, we delivered CPSF3 inhibitor JTE-607 into the brain of mice using a drug sustained release pump, which significantly inhibited tumor growth.
To sum up, RBBP6 mediating variable of adenosine acidification regulatory protein polymer CPSF3 K63 of ubiquitin polymer. Knockout RBBP6 accelerate the degradation of CPSF3, lead to competitive key MYC oncogene endogenous RNA (ceRNA) 3 'UTR shortened, release free of micrornas inhibit the expression of MYC, thereby inhibiting the growth of glioblastoma. The study confirmed the RBBP6 control variable of adenosine polymer acidification effect the expression of MYC, targeted RBBP6 - CPSF3 shaft can inhibit the growth of glioblastoma, potential therapeutic targets for glioblastoma provides support.
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