BUB1B and circBUB1B_544aa aggravate multiple myeloma malignancy through evoking chromosomal instability

Abstract

Multiple myeloma (MM) is an incurable plasma cell malignancy in the bone marrow characterized by chromosome instability (CIN), which contributes to the acquisition of heterogeneity, along with MM progression, drug resistance, and relapse. In this study, we elucidated that the expression of BUB1B increased strikingly in MM patients and was closely correlated with poor outcomes. Overexpression of BUB1B facilitated cellular proliferation and induced drug resistance in vitro and in vivo, while genetic targeting BUB1B abrogated this effect. Mechanistic studies unveiled that enforced expression of BUB1B evoked CIN resulting in MM poor outcomes mainly through phosphorylating CEP170. Interestingly, we discovered the existence of circBUB1B_544aa containing the kinase catalytic center of BUB1B, which was translated by a circular RNA of BUB1B. The circBUB1B_544aa elevated in MM peripheral blood samples was closely associated with MM poor outcomes and played a synergistic effect with BUB1B on evoking CIN. In addition, MM cells could secrete circBUB1B_544aa and interfere the MM microenvironmental cells in the same manner as BUB1B full-length protein. Intriguingly, BUB1B siRNA, targeting the kinase catalytic center of both BUB1B and circBUB1B_544aa, significantly inhibited MM malignancy in vitro and in vivo. Collectively, BUB1B and circBUB1B_544aa are promising prognostic and therapeutic targets of MM.

Diagnostic, Prognostic, and Immunological Roles of HELLS in Pan-Cancer: A Bioinformatics Analysis

“…Among these hub genes, MAD2L1, TOP2A, NCAPG, TTK, KIF11, HELLS, and RRM2 may affect biological changes after receiving second messengers from activated BUB1B, DTL, and CDK1. BUB1B encodes a kinase involved in spindle checkpoint function, whose impairment is associated with various cancers ( 27 – 30 ). CDK1 encodes the catalytic subunit of a highly conserved protein kinase complex that is required for the G1/S and G2/M phase transitions of the eukaryotic cell cycle.…”

Screening of the Key Genes for the Progression of Liver Cirrhosis to Hepatocellular Carcinoma Based on Bioinformatics

“…We have identified BUB1B, NUSAP1, TTK, HMMR, CCNA2, and KIF2C as potential predictive markers for HCC. Previous studies indicate that expression levels of BUB1B, which is a spindle-assembly checkpoint gene [ 26 ], were highly upregulated in multiple myeloma patients and that these levels were strongly correlated with unfavorable outcomes [ 27 ]. Another marker, NUSAP1, which is a microtubule-associated protein involved in mitosis, is also known to participate in cell proliferation, apoptosis, and repairing DNA damage in glioblastoma multiforme cells [ 28 ].…”

Candidate biomarkers for diagnosis and prognosis of prostate cancer based on bioinformatics methods

“…Pure-hybrid BUB1B mutations could lead to autosomal recessive gastrointestinal cancer susceptibility [32]. Further, BUB1B expression was signi cantly increased in patients with multiple myeloma and was strongly associated with poor outcomes [33]. In another study, BUB1B was shown to be a predictive marker for aggressiveness and effective drug response in glioblastoma [34].…”