System Analysis Identifies MYBL2 As a Novel Oncogene Target for Metastatic Prostate Cancer.

Abstract

Bone metastasis significantly contributes to the unfavorable prognosis observed in patients with prostate cancer. MYB proto-oncogene like 2 (MYBL2) has been identified as a potential target gene implicated in tumor progression. Nevertheless, the oncogenic role and underlying mechanisms of MYBL2 in bone metastasis of prostate cancer (PCa) have yet to be elucidated. Bioinformatics analyses were employed to identify genes pivotal to metastatic PCa. Subsequently, a series of molecular biology experiments in vitro, alongside a model of PCa bone metastasis in vivo, were utilized to validate the pro-metastatic effects and underlying mechanisms of MYBL2. A bioinformatics analysis identified a candidate set of 72 genes, which was used to establish a PFS prognostic model highlighting 16 key genes. Based on the expression of these 16 key genes, 498 patients with PCa from the TCGA database were divided into four subgroups. Patients in the C1 and C4 subgroups had poorer prognoses. Through the analysis of sequencing data from the C1 and C4 cohorts in comparison to the C2 and C3 cohorts, we identified MYBL2 as a critical prognostic gene in metastatic PCa. Notably, we found that MYBL2 was significantly expressed in metastatic PCa and positively related to poor prognosis. Mechanistic studies revealed that MYBL2 overexpression promoted PCa cells invasion and EMT, while NOTCH3 knockdown partly abrogated that. Moreover, MYBL2 overexpression can promote PCa xenograft growth and bone metastasis in vivo. This study found that MYBL2 overexpression in PCa were positively related to metastasis and poor prognosis. MYBL2 promoted PCa bone metastasis via activating NOTCH3. Targeting the MYBL2/NOTCH3 axis could help prevent metastatic PCa.