The emerging role of mediator complex subunit 12 in tumorigenesis and response to chemotherapeutics

Abstract

Transcriptional dysregulation induced by disease‐defining genetic alterations of proteins in transcriptional machinery is a key feature of cancers. Mediator complex subunit 12 (MED12) is the central architectural subunit in the kinase module of Mediator, a large transcriptional regulatory complex that controls essential steps of transcription. Emerging evidence links deregulated MED12 to human cancers. MED12 is frequently mutated in benign tumors and cancers. Although the missense mutations of MED12 in benign tumors disrupt the kinase activity of Mediator, MED12 mutations in cancers could eliminate the interaction between Mediator complex and RNA polymerase II, leading to severe transcriptional misregulation. Aberrant expression of MED12 is associated with the prognosis of various types of human cancers. Loss of MED12 function has been associated with the development of resistance to chemotherapeutics. Moreover, MED12 is modified by posttranscriptional regulations. Arginine methylation of MED12 has been shown to regulate MED12‐mediated transcriptional regulation and response to chemotherapeutics in human cancer cell lines. In this mini‐review, the authors provide an overview of the roles of MED12 in the development of benign and malignant tumors as well as its roles in chemoresistance. The studies of MED12 exemplify that aberrant transcriptional programming is a therapeutic vulnerability for certain types of cancer.

Divergent clonal evolution of blastic plasmacytoid dendritic cell neoplasm and chronic myelomonocytic leukemia from a shared TET2-mutated origin

“…We also identified MED12 p.Gly44Ser in BPDCN for the first time, as a novel candidate “secondary” driver mutation. This hotspot mutation occurs frequently (~70–80%) in uterine leiomyoma and breast fibroepithelial tumors (plus their malignant equivalents), 5–10% of chronic lymphocytic leukemias, and sporadically in other cancers [ 11 ]. Intriguingly, the highest MED12 expression in hematopoiesis is reportedly in pDCs (Supplementary Fig.…”

MED13L integrates Mediator-regulated epigenetic control into lung cancer radiosensitivity

“…Cancer cells often arise as a consequence of dysregulation of gene expression, such as the upregulated expression of oncogenes. Therefore, Mediator dysfunction is implicated in malignancies 11 - 13 . The cyclin-dependent kinase 8 (CDK8) kinase module reversibly interacts with the core Mediator through MED13, causing further modulation of Mediator's functions 1 , 5 , 14 , 15 .…”

Genome-wide screens identify specific drivers of mutant hTERT promoters

“…These results further confirm the efficiency of our screening and the validity of our reporter lines generated for the hTERT promoter activity quantification. MED12 gain of function mutations are observed in human cancers ( 50 , 51 ). Targeting MED12 could be an advantage in cancers like phyllodes tumors where MED12 and hTERT promoter mutations cooccur ( 52 , 53 ).…”