TY - JOUR
T1 - Modulation of DNA Damage Response by SAM and HD Domain Containing Deoxynucleoside Triphosphate Triphosphohydrolase (SAMHD1) Determines Prognosis and Treatment Efficacy in Different Solid Tumor Types
AU - Romeo, Margarita
AU - Gómez, Maica
AU - Riveira-Muñoz, Eva
AU - Felip, Eudald
AU - Perez-Roca, Laia
AU - Margeli Vila, Mireia
AU - Clotet, Bonaventura
AU - Ballana, Ester
AU - Mesía, Ricard
AU - Martinez-Cardus, Anna
AU - Fernandez Ruiz, Pedro Luis
AU - Layos, Laura
AU - Garcia-Vidal, Edurne
AU - Gutiérrez-Chamorro, Lucía
AU - Moran Bueno, Teresa
N1 - This research was supported by grants from Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (FIS) PI17/00624, and PI19/00194, co-financed by FEDER. E.F. and E.B. are research fellows from ISCIII-FIS (CM20/00027 and MSII19/00012, respectively). L.G.-C. is a research fellow from Generalitat de Catalunya AGAUR. E.G.-V. is a research fellow from PERIS (SLT017/20/000090). We thank Foundation Dormeur for financial support for the acquisition of the QuantStudio-5 real-time PCR system.
PY - 2022/1/27
Y1 - 2022/1/27
N2 - SAMHD1 is a deoxynucleotide triphosphate (dNTP) triphosphohydrolase with important roles in the control of cell proliferation and apoptosis, either through the regulation of intracellular dNTPs levels or the modulation of the DNA damage response. However, SAMHD1′s role in cancer evolution is still unknown. We performed the first in-depth study of SAMHD1′s role in advanced solid tumors, by analyzing samples of 128 patients treated with chemotherapy agents based on platinum derivatives and/or antimetabolites, developing novel in vitro knock-out models to explore the mechanisms driving SAMHD1 function in cancer. Low (or no) expression of SAMHD1 was associated with a positive prognosis in breast, ovarian, and non-small cell lung cancer (NSCLC) cancer patients. A predictive value was associated with low-SAMHD1 expression in NSCLC and ovarian patients treated with antimetabolites in combination with platinum derivatives. In vitro, SAMHD1 knock-out cells showed increased γ-H2AX and apoptosis, suggesting that SAMHD1 depletion induces DNA damage leading to cell death. In vitro treatment with platinum-derived drugs significantly enhanced γ-H2AX and apoptotic markers expression in knock-out cells, indicating a synergic effect of SAMHD1 depletion and platinum-based treatment. SAMHD1 expression represents a new strong prognostic and predictive biomarker in solid tumors and, thus, modulation of the SAMHD1 function may constitute a promising target for the improvement of cancer therapy.
AB - SAMHD1 is a deoxynucleotide triphosphate (dNTP) triphosphohydrolase with important roles in the control of cell proliferation and apoptosis, either through the regulation of intracellular dNTPs levels or the modulation of the DNA damage response. However, SAMHD1′s role in cancer evolution is still unknown. We performed the first in-depth study of SAMHD1′s role in advanced solid tumors, by analyzing samples of 128 patients treated with chemotherapy agents based on platinum derivatives and/or antimetabolites, developing novel in vitro knock-out models to explore the mechanisms driving SAMHD1 function in cancer. Low (or no) expression of SAMHD1 was associated with a positive prognosis in breast, ovarian, and non-small cell lung cancer (NSCLC) cancer patients. A predictive value was associated with low-SAMHD1 expression in NSCLC and ovarian patients treated with antimetabolites in combination with platinum derivatives. In vitro, SAMHD1 knock-out cells showed increased γ-H2AX and apoptosis, suggesting that SAMHD1 depletion induces DNA damage leading to cell death. In vitro treatment with platinum-derived drugs significantly enhanced γ-H2AX and apoptotic markers expression in knock-out cells, indicating a synergic effect of SAMHD1 depletion and platinum-based treatment. SAMHD1 expression represents a new strong prognostic and predictive biomarker in solid tumors and, thus, modulation of the SAMHD1 function may constitute a promising target for the improvement of cancer therapy.
KW - NSCLC
KW - Breast cancer
KW - Solid tumors
KW - SAMHD1
KW - Ovarian cancer
UR - https://www.mdpi.com/2072-6694/14/3/641
U2 - 10.20944/preprints202201.0141.v1
DO - 10.20944/preprints202201.0141.v1
M3 - Article
C2 - 35158911
SN - 2072-6694
VL - 14
JO - Cancers
JF - Cancers
IS - 3
M1 - 641
ER -