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Loss of a cohesin-linked suppressor APRIN (Pds5b) disrupts stem cell programs in embryonal carcinoma: an emerging cohesin role in tumor suppression

Oncogene volume 29, pages 3446–3452 (2010)Cite this article

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Abstract

Cohesins appear to have critical functions beyond mitotic cohesion. Our data on a cohesin-associated Pds5-paralog, APRIN, indicate a novel cohesin role in stem cell differentiation. APRIN/Pds5B is lost in many cancers and it is a putative tumor suppressor. Its mutations in the germ line, however, generate birth defects. We reasoned that as both cancer and birth defects share disrupted stem cell differentiation, the data suggest an APRIN/Pds5B cohesin function in stem cells. We used an embryonal carcinoma stem cell model and show here that (i) APRIN expression is precisely coordinated with stem cell differentiation; (ii) this coordination involves surface-contact and endocrine pathways; and (iii) APRIN/Pds5b coordination is critical in stem/progenitor exit decisions. APRIN knockdown disrupted Oct4, Nanog and SOX2 patterns, differentiation failed and the resulting immature proliferative cells did not progress beyond proneural progenitor phase. Furthermore, the phenotype—blocked progenitor exit (Mash-1+); failed E-cadherin exit (E-Cadhlow+); incomplete N-cadherin transition (N-Cadhlow+); retained proliferative capacity (c-myc+); irregular stemness (SOX2late++) and lost response to contact and hormonal cues—shares similarities with cancer-initiating cells. The data suggest novel APRIN/Pds5B-linked cohesin roles in stem/progenitor programs and a new mechanism in tumor suppression.

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Acknowledgements

We are grateful to Grace Gill, Karina Meiri and Natasha Kreder for critical review of the paper. The technical assistance of Shu Ling Liang and Byung Kyu Kim is greatly appreciated. This work was supported by the following awards: DOD-DAMD17–01–1–0430 (PG); DOD-DAMD17–03–1–0266 (PG); The Susan G Komen Breast Cancer Foundation BCTR0403214 (PG); W81XWH-08–1–0575 (PG); W81XWH-09–1–0411 (PG) and Sanofi-Aventis award IST10257 (AM).

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  1. V Denes

    Present address: 4Current address: Department of Experimental Zoology and Neurobiology, University of Pécs, Pécs, Ifjúság u. 6. Hungary H-7601.,

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, Tufts University School of Medicine, Boston, MA, USA

    V Denes & P Geck

  2. Department of Pathology, Tufts Medical Center, Boston, MA, USA

    M Pilichowska

  3. Department of Urology, Tufts Medical Center, Boston, MA, USA

    A Makarovskiy & G Carpinito

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Correspondence to P Geck.

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Denes, V., Pilichowska, M., Makarovskiy, A. et al. Loss of a cohesin-linked suppressor APRIN (Pds5b) disrupts stem cell programs in embryonal carcinoma: an emerging cohesin role in tumor suppression. Oncogene 29, 3446–3452 (2010). https://doi.org/10.1038/onc.2010.100

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