ABSTRACT
Sterile α motif and HD domain-containing protein 1 (SAMHD1) is a mammalian dNTP hydrolase (dNTPase) that regulates intracellular dNTP balance. We have previously reported that SAMHD1 mRNA and protein levels are significantly downregulated in CD4+ T-cells of patients with cutaneous T-cell lymphoma (CTCL), a disease characterized by infiltration of neoplastic CD4+ T-lymphocytes into the skin. However, functional significance of SAMHD1 in CTCL development and progression remains unknown. Here we investigate the mechanism by which SAMHD1 induces apoptosis in CTCL-derived CD4+ T-cells. We stably expressed exogenous SAMHD1 in the CTCL-derived HuT78 T-cell line containing a very low level of endogenous SAMHD1 protein. We found that low-level exogenous expression of SAMHD1 led to a significant reduction in HuT78 cell growth, proliferation, and colony formation. Exogenous SAMHD1 expression in HuT78 cells also resulted in increased spontaneous and Fas ligand (Fas-L)-induced apoptosis levels via activation of the extrinsic pathway, including caspase-8, −3 and −7. Additionally, increased SAMHD1 significantly reduced the protein and mRNA expression of the short isoform of cFLIP (cFLIPS), an important negative regulator of Fas-L-mediated apoptotic signaling. Our results indicate that exogenous SAMHD1 expression inhibits HuT78 cell growth and proliferation in part by increasing apoptosis. These findings implicate that SAMHD1 acts as an inhibitor in CTCL cell growth, suggesting that downregulation of SAMHD1 expression in neoplastic T-cells can facilitate uncontrolled cell proliferation.
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Acknowledgments
We thank Rebeca Kohnken and the Wu lab members for valuable discussions, and Giovanna Merchand Reyes for technical assistance.
Funding
This work was supported by a NIH grant (CA181997) to LW. LW is also supported in part by NIH grants (AI104483, AI120209, and AI127667) and the Public Health Preparedness for Infectious Diseases Program of the Ohio State University.
Authors' contributions
LW conceived the study and designed experiments with KMK. KMK performed experiments and analyzed data with LW. ML and SL generated SAMHD1-expressing HuT78 cell line. KMK and LW wrote the manuscript. All the authors read and approved the manuscript.