Abstract
Embryonal carcinomas (ECs) and seminomas are testicular germ cell tumors. ECs display expression of SOX2, while seminomas display expression of SOX17. In somatic differentiation, SOX17 drives endodermal cell fate. However, seminomas lack expression of endoderm markers, but show features of pluripotency. Here, we use chromatin immunoprecipitation sequencing to report and compare the binding pattern of SOX17 in seminoma-like TCam-2 cells to SOX17 in somatic cells and SOX2 in EC-like 2102EP cells. In seminoma-like cells, SOX17 was detected at canonical (SOX2/OCT4), compressed (SOX17/OCT4) and noncomposite SOX motifs. SOX17 regulates TFAP2C, PRDM1 and PRDM14, thereby maintaining latent pluripotency and suppressing somatic differentiation. In contrast, in somatic cells canonical motifs are rarely bound by SOX17. In sum, only 12% of SOX17-binding sites overlap in seminoma-like and somatic cells. This illustrates that binding site choice is highly dynamic and cell type specific. Deletion of SOX17 in seminoma-like cells resulted in loss of pluripotency, marked by a reduction of OCT4 protein level and loss of alkaline phosphatase activity. Furthermore, we found that in EC-like cells SOX2 regulates pluripotency-associated genes, most likely by partnering with OCT4. In conclusion, SOX17 (in seminomas) functionally replaces SOX2 (in ECs) to maintain expression of the pluripotency cluster.
Highlights
Testicular cancer is the most common malignancy in young men 1
We demonstrated that both transcription factors bind to canonical motifs by partnering with OCT4, as well as to SOX-family DNA binding motifs
This way SOX17 and SOX2 regulate a common set of pluripotency and germ cell-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6)
Summary
Testicular cancer is the most common malignancy in young men 1. The most frequent testicular tumours are the type II germ cell tumours (TGCTs). Morphology and marker expression TGCTs are classified as seminomas or non-seminomas 1. Non-seminomas initially present as embryonal carcinomas (ECs), which can further differentiate into mixed non-seminoma 1. Seminomas and ECs arise from the same precursor lesion (germ cell neoplasia in situ / GCNIS), which is believed to result from primordial germ cells (PGCs) arrested in development 2. Seminomas retain to the most part the genetic and epigenetic signature of PGCs i.e. they express pluripotency (LIN28, NANOG, POU5F1 (OCT4)) and PGC (PRDM1, TFAP2C, DMRT1, cKIT, SOX17) markers 3. The gene expression profile of ECs is highly similar to embryonic stem cells (ESCs), hallmarked by expression of pluripotency markers (LIN28, NANOG, POU5F1 (OCT4), TFAP2C, GDF3, DNMT3B, TDGF1, SOX2) 3. Seminomas are SOX17+ and SOX2-, while ECs are SOX17- and SOX2+ 4
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