The Cellular Consequences of PASD1 Expression in Human Cancer
Abstract
ABSTRACT
The Cellular Consequences of PASD1 Expression in Human Cancer
Ashley M. Kern
There are nearly 1,000 human proteins that are expressed only in the germline. Cancer /Testis antigens (CT antigens) represent a subset of germline-specific proteins that become reactivated in somatic cells that have undergone oncogenic transformation. Human PAS Domain containing protein 1 (PASD1) is an X-linked CT Antigen. In 2015, the Partch Laboratory established that PASD1 prevents the core circadian transcription factor, CLOCK:BMAL1, from rhythmically transcribing its target genes to suppress circadian rhythms after it becomes upregulated in cancer cells. In addition to this striking phenotype, PASD1 also promotes mitotic defects that could favor tumor progression. These phenotypes may go hand in hand; over 43% of the mammalian genome, including many cell cycle genes, is under circadian control. In this study, we found that expression of PASD1, promotes mitotic arrest, slows DNA replication, and diminishes the effects of mitotic spindle poisoning. Interestingly, preliminary data demonstrate that PASD1 is natively expressed in spermatogonia, which are testicular stem cells that undergo repeated asymmetric mitotic divisions to give rise to progenitor cells. These data support the hypothesis that expression of PASD1 in somatic cancer cells promotes premature mitotic entry, which could promote oncogenic transformation in somatic cells. The cell cycle phenotypes we observe in our study could be a consequence of reactivating the native functions of PASD1. Further studies will be required to determine if these phenotypes are due to PASD1-mediated clock repression, or whether they arise from distinct cellular pathways regulated by PASD1 in somatic cancer cells.