Functional analysis of the histone arginine methyltransferase PRMT6
Aberrant expression of several PRMTs is linked to the pathogenesis of human cancer. PRMTs catalyse the arginine methylation of many substrates, which are implicated in cancer development, progression and aggressiveness. In this context, only few studies investigated PRMT6 so far and its possible rol...
Molekularbiologie und Tumorforschung
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|Summary:||Aberrant expression of several PRMTs is linked to the pathogenesis of human cancer. PRMTs catalyse the arginine methylation of many substrates, which are implicated in cancer development, progression and aggressiveness. In this context, only few studies investigated PRMT6 so far and its possible role in tumourigenesis and the control of cellular processes, which could also be deregulated in human cancer by PRMT6. Hence, the present study analysed the expression of PRMT6 in murine lung cancer, tried to reveal the role of PRMT6 in cell proliferation and senescence and continued the validation of putative interaction partners of PRMT6.
In the first part of this thesis, immunohistochemical (IHC) stainings demonstrated that Prmt6 protein levels are predominantly increased in lung tumour cells compared to healthy tissue using the LLC1 and KrasLA2 mouse models. The second part of this thesis showed that PRMT6 negatively regulates the transcriptional expression of the tumour suppressor genes CDKN1A and p16-INK4A. Both are direct target genes of PRMT6, whereby the corresponding histone mark H3R2me2a is exclusively enriched at the CDKN1A gene. Knockdown of PRMT6 results in proliferation defects of several transformed cell lines and induces a senescent phenotype in non-transformed human diploid fibroblasts. Furthermore, PRMT6 was found to inhibit the onset of oncogene-induced senescence (OIS), in which CDKN1A is an activator of the senescent phenotype. In the third part of this thesis, PRMT6 was shown to interact with PCNA, DDB1 and DDB2. These interactors are subunits of the CUL4A-RING ubiquitin E3-ligase complex (CRL4) and hint to possible novel cellular functions of PRMT6 in the ubiquitylation processes either after DNA damage or during replication and transcription.
In summary, the present study reveals that PRMT6 is overexpressed in murine lung cancer. It uncovers novel functional aspects of PRMT6 being a positive regulator of proliferation and negative regulator of senescence by transcriptional repression of tumour suppressor genes. Finally, it opens up a field of so far undescribed possible functions of PRMT6 by validation of novel interaction partners of PRMT6.|