Zhong Feiliang, Liu Jia, Gao Chang, Chen Tingting, Li Bo
Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Tianjin, China.
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin University, Tianjin, China.
Front Oncol. 2022 May 18;12:816070. doi: 10.3389/fonc.2022.816070. eCollection 2022.
The transcription factor MYBL2 is widely expressed in proliferating cells. Aberrant expression of MYBL2 contributes to tumor malignancy and is associated with poor patient prognosis. However, the downstream transcriptional network that mediates its oncogenic properties remains elusive. In the present study, we observed that MYBL2 was overexpressed in malignant and metastatic melanoma patient samples and that the high expression level of MYBL2 was significantly associated with poor prognosis. A loss-of-function study demonstrated that MYBL2 depletion significantly decreased cell proliferation and migration and prevented cell cycle progression. We also determined that MYBL2 promoted the formation of melanoma stem-like cell populations, indicating its potential as a therapeutic target for treating resistant melanoma. Mechanistically, we constructed an MYBL2 regulatory network in melanoma by integrating RNA-seq and ChIP-seq data. EPPK1, PDE3A, and FCGR2A were identified as three core target genes of MYBL2. Importantly, multivariate Cox regression and survival curve analysis revealed that PDE3A and EPPK1 were negatively correlated with melanoma patient survival; however, FCGR2A was positively correlated with patient survival. Overall, our findings elucidate an MYBL2 regulatory network related to cell proliferation and cancer development in melanoma, suggesting that MYBL2 may be potentially targeted for melanoma diagnosis and treatment.
转录因子MYBL2在增殖细胞中广泛表达。MYBL2的异常表达会导致肿瘤恶性化，并与患者预后不良相关。然而，介导其致癌特性的下游转录网络仍不清楚。在本研究中，我们观察到MYBL2在恶性和转移性黑色素瘤患者样本中过表达，且MYBL2的高表达水平与预后不良显著相关。一项功能丧失研究表明，MYBL2缺失显著降低细胞增殖和迁移，并阻止细胞周期进程。我们还确定MYBL2促进黑色素瘤干细胞样细胞群体的形成，表明其作为治疗耐药性黑色素瘤的治疗靶点的潜力。从机制上讲，我们通过整合RNA-seq和ChIP-seq数据构建了黑色素瘤中的MYBL2调控网络。EPPK1、PDE3A和FCGR2A被鉴定为MYBL2的三个核心靶基因。重要的是，多变量Cox回归和生存曲线分析显示，PDE3A和EPPK1与黑色素瘤患者生存呈负相关；然而，FCGR2A与患者生存呈正相关。总体而言，我们的研究结果阐明了一个与黑色素瘤细胞增殖和癌症发展相关的MYBL2调控网络，表明MYBL2可能是黑色素瘤诊断和治疗的潜在靶点。
