Oncogenic action of the exosome cofactor RBM7 by stabilization of CDK1 mRNA in breast cancer

Abstract

RNA exosome can target the specific RNAs for their processing/degradation by distinct exosome cofactors. As a key component in exosome cofactors, RNA binding motif protein 7 (RBM7) shows the binding specificity for uridine-rich sequences in mRNAs via its RNA recognition motifs. However, the specific function of RBM7 in human breast cancer remains unclear. In vitro, experiments revealed that knockdown of RBM7 dramatically inhibited breast cancer cell proliferation, while inducing G1 cell cycle arrest; the opposite was true when RBM7 was overexpressed. Meanwhile, experiments in vivo confirmed the oncogenic function of RBM7 in breast cancer. RNA sequencing and the following pathway analysis found that cyclin-dependent kinase1 (CDK1) was one of the main gene regulated by RBM7. Overexpression of RBM7 increased CDK1 expression, while RBM7 knockdown decreased it. RIP assays additionally found that RBM7 bound directly to CDK1 mRNA. It was also showed that RBM7 could directly bind to the AU-rich elements (AREs) in 3′-UTR of CDK1 mRNA, which contributed to the stability of CDK1 mRNA by lengthening its half-life. More importantly, the oncogenic activity reduced by knockdown of RBM7 could be rescued by overexpression of CDK1 both in vitro and in vivo, but mutant CDK1 failed. All the evidences implied RBM7 promoted breast cancer cell proliferation by stabilizing CDK1 mRNA via binding to AREs in its 3′-UTR. As we knew, it was the first attempt to connect the RNA exosome to the tumor development, providing new insights into the mechanisms of RNA exosome-linked diseases.

Dihydroartemisinin Suppresses the Tumorigenesis and Cycle Progression of Colorectal Cancer by Targeting CDK1/CCNB1/PLK1 Signaling

“…It has been proven that CDK1 is connected to poor prognosis and cancer progression. It can initiate tumorigenesis of melanoma with the cooperation of Sox2 ( 44 ), and the stabilization of CDK1 is required for breast cancer cell proliferation ( 45 ). CDK1 also regulates the proliferation of gastric cancer via binding with CCNB1 and CCNB2 ( 46 ).…”

Tumor Microenvironment Subtypes and Immune‐Related Signatures for the Prognosis of Breast Cancer

“…MKI67 has been regarded as a contributing component for molecular heterogeneity of breast cancer validated by previous studies [21,22]. As an essential regulator for the cell cycle, the activity of CDK1 has long been considered a potential target, which is associated with cell cycle dysfunction and corresponding distinct molecular profiles of breast cancer [23]. These findings were in accordance with the current researches of TTK [24], CDC20 [25], PLK1 [26], and AURKA [27], which were considered the leading contributors for molecular heterogeneity genesis in the current study.…”

CircMETTL3, upregulated in a m6A-dependent manner, promotes breast cancer progression

“…Through bioinformatics analysis, we identified CDK1 as a potential target of miR-31-5p, which was confirmed by luciferase reporter assay. CDK1, a member of the CDKs, plays a critical role in different types of cancers 21 , 28 - 30 . The other study showed CDK1 acted as a novel prognostic indicator for early breast cancer 31 .…”