Bhole Ritesh, Shinkar Jagruti, Labhade Sonali, Karwa Pawan, Kapare Harshad
Dr. D.Y. Patil Institute of Pharmaceutical Sciences and Research, Pune, 411018, Maharashtra, India.
Dr. D.Y. Patil Dental College and Hospital, Dr. D.Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, India.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Mar 19. doi: 10.1007/s00210-025-04006-0.
MED12, a critical subunit of the mediator (MED) complex, plays a central role in transcriptional regulation by bridging signal-dependent transcription factors and RNA polymerase II. Dysregulation of MED12, often through mutation, has emerged as a significant driver in various cancers, including uterine leiomyomas, breast cancer (B.C.), and prostate cancer (P.C.). These mutations disrupt normal transcriptional processes by impairing the mediator complex's ability to properly regulate gene expression, which activates oncogenic pathways such as Wnt/β-catenin and TGF-β signaling, promoting tumorigenesis and drug resistance. Specifically, mutations in the MED12 gene lead to altered interactions with the transcriptional machinery, fostering aberrant activation of oncogenic networks. MED12 alterations have also been implicated in chemoresistance, particularly to therapies targeting EGFR, ALK, and BRAF, highlighting its role as a barrier to effective treatment. This review explores the mechanisms underlying MED12 dysregulation, its impact on cancer progression, and its association with therapeutic resistance. By examining its potential as a predictive biomarker and a therapeutic target, the article underscores the importance of MED12 in advancing precision oncology. Understanding MED12-mediated mechanisms offers insights into overcoming therapeutic resistance and paves the way for innovative, personalized cancer treatments.
MED12是中介体（MED）复合物的关键亚基，通过连接信号依赖性转录因子和RNA聚合酶II在转录调控中发挥核心作用。MED12的失调，通常是通过突变，已成为包括子宫平滑肌瘤、乳腺癌（B.C.）和前列腺癌（P.C.）在内的各种癌症的重要驱动因素。这些突变通过损害中介体复合物正确调节基因表达的能力来破坏正常的转录过程，从而激活致癌途径，如Wnt/β-连环蛋白和TGF-β信号通路，促进肿瘤发生和耐药性。具体而言，MED12基因的突变导致与转录机制的相互作用改变，促进致癌网络的异常激活。MED12改变也与化疗耐药性有关，特别是对靶向EGFR、ALK和BRAF的疗法，突出了其作为有效治疗障碍的作用。本综述探讨了MED12失调的潜在机制、其对癌症进展的影响以及与治疗耐药性的关联。通过研究其作为预测生物标志物和治疗靶点的潜力，本文强调了MED12在推进精准肿瘤学方面的重要性。了解MED12介导的机制有助于深入了解克服治疗耐药性，并为创新的个性化癌症治疗铺平道路。
