Abstract
MyoD family inhibitor (MDFI) and MDFI domain-containing (MDFIC) are homologous proteins known to regulate myogenic transcription factors. Hitherto, their role in cancer is unknown. We discovered that MDFI is up- and MDFIC downregulated in colorectal tumors. Mirroring these different expression patterns, MDFI stimulated and MDFIC inhibited growth of HCT116 colorectal cancer cells. Further, MDFI and MDFIC interacted with Jumonji C domain-containing (JMJD) 1 A, a histone demethylase and epigenetic regulator involved in colorectal cancer. JMJD1A influenced transcription of several genes that were also regulated by MDFI or MDFIC. Notably, the HIC1 tumor suppressor gene was stimulated by JMJD1A and MDFIC, but not by MDFI, and HIC1 overexpression phenocopied the growth suppressive effects of MDFIC in HCT116 cells. Similar to colorectal cancer, MDFI was up- and MDFIC downregulated in breast, ovarian and prostate cancer, but both were overexpressed in brain, gastric and pancreatic tumors that implies MDFIC to also promote tumorigenesis in certain tissues. Altogether, our data suggest a tumor modulating function for MDFI and MDFIC in colorectal and other cancers that may involve their interaction with JMJD1A and a MDFIC→HIC1 axis.
Highlights
MyoD family inhibitor (MDFI; known as I-mfa for inhibitor of MyoD family A) was originally cloned as an interaction partner of the MyoD family of myogenic transcription factors
We found that MDFI and MyoD family inhibitor domain-containing (MDFIC) are capable of interacting with JMJD1A, a member of the Jumonji C domain-containing (JMJD) protein family
When Flag-tagged MDFI was coexpressed with HA-tagged JMJD1A, MDFI coprecipitated with JMJD1A, but not with the homologous JMJD1B or two other JMJD proteins, UTX and PHF2 (Fig. 1a and Supplementary Fig. S1a)
Summary
MyoD family inhibitor (MDFI; known as I-mfa for inhibitor of MyoD family A) was originally cloned as an interaction partner of the MyoD family of myogenic transcription factors. MDFI represses their ability to activate gene transcription likely by two mechanisms: retention of these myogenic factors in the cytoplasm and inhibition of their nuclear DNA binding activity[1]. Similar to its inhibitory impact on the MyoD family, MDFI binds to and suppresses the activity of the TCF/LEF-1 transcription factor that is a downstream effector in the WNT/β-catenin signaling pathway. On a 129/Sv background, Mdfi−/− mice can survive into adulthood and be fertile; but various degrees of mild spina bifida and skeletal defects affecting the ribs were reported, with the most severe phenotypes causing death shortly after birth[7] Another function of MDFI has been observed in osteoclasts: their number is increased and bone density reduced in Mdfi−/− mice[8]. We examined the role of MDFI and MDFIC in colorectal cancer cells
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