Zrf1’s role in mESC differentiation and breast cancer progression
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Abstract
Zuotin-related factor 1 (Zrf1) has recently been identified as an epigenetic regulator of gene transcription. Upon a differentiation stimulus, Zrf1 facilitates the expression of its target genes via specifically binding to mono-ubiquitinated histone H2A and simultaneous displacement of PRC1 from chromatin. So far, Zrf1 was shown to primarily operate during differentiation into the neuronal lineage. As a multifunctional protein, Zrf1 plays a crucial role in carcinogenesis. Zrf1 is overexpressed in many cancers and was suggested to have an oncogenic role in cancer progression. Zrf1 provides leukemogenic potential in acute myeloid leukemia and it contributes to Ras-oncogene induced senescence through the INK4-ARF locus.
In the present study, I elucidated a broader role for Zrf1 during during in vitro differentiation. Zrf1 depleted mESCs have defects in the generation of all three germ layers. I observed a particularly pronounced effect during mesoderm development and I was able to rescue the observed phenotype by re-expression of Zrf1 in Zrf1 knockdown cells. I found that Zrf1 plays a prominent role in cardiomyocyte differentiation and Zrf1 knockdown results in impaired beating function of cardiomyocytes in vitro. At the molecular level, Zrf1 plays an essential regulatory role for the expression of the first and second heart field related genes, thereby promoting faithful cardiomyocyte differentiation. Taken together, the function of Zrf1 needs to be considered when addressing molecular mechanisms of cardiovascular diseases.
In addition to studying the function of Zrf1 during differentiation, I have studied the function of Zrf1 in breast invasive ductal carcinoma. Upon Zrf1 depletion, breast cancer cells increase their cell motility, decrease their cellular adhesion and are able to form organoid like structures in cell suspension. Hence, Zrf1 depleted cells can mimic the events during cancer metastasis in vitro. Zrf1 knockdown also contributes to hormone independent growth of cells which represents a phenotype that is observed in more aggressive forms of breast cancer. Zrf1 depletion disrupts the balance between anti-apoptotic and pro-apoptotic genes, thereby favoring cell survival and contributing to drug resistance. My data suggest that Zrf1 is a potential novel target to be explored for new treatment strategies in breast cancer, moreover it plays a critical regulatory role in the progression of breast invasive ductal carcinoma.