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

Abstract

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.

SAMHD1 silencing cooperates with radiotherapy to enhance anti-tumor immunity through IFI16-STING pathway in lung adenocarcinoma

“…In the colorectal cancer, high expression SAMHD1 correlated with metastasis [ 30 ] and indicated poor prognosis of stage II patients [ 31 ]. Consistent with our results, Eudald Felip et al found that low expression of SAMHD1 was associated with a positive prognosis in breast, ovarian and non-small cell lung cancer patients [ 32 ].…”

SAMHD1 expression modulates innate immune activation and correlates with ovarian cancer prognosis

“…In view of these findings, the role of SAMHD1 was also evaluated in a cohort of 22 ovarian cancer patients, previously described (11).…”

“…T47D cells were obtained from Sigma-Aldrich-ECACC (European Collection of Authenticated cell cultures, 85102201-1VL) and grown in complete Dulbecco’s modified Eagle’s medium (DMEM, ThermoFischer) supplemented with 10% of heat-inactivated fetal bovine serum (FBS, ThermoFisher) and antibiotics 100 U/ml penicillin, 100 μg/ml streptomycin (Life Technologies) and maintained at 37°C in a 5% CO 2 incubator. For generation of knock-out (KO) cells, T47D cells were transfected with a plasmid expressing a CRISPR-Cas9 construct designed to disrupt the sequence corresponding to exon 5 of SAMHD1 gene that encodes for HD domain (CRISPR-SAMHD1), as described previously ( 11 ).…”

“…Thus, a better understanding of nucleic acid sensing pathways, including upstream and downstream regulators, is key for a better understanding of ovarian cancer immunity, the identification of novel putative therapeutic targets and the development of new potential therapeutic approaches. SAMHD1 (sterile alpha motif and histidine/aspartic acid domaincontaining protein 1) is a cellular deoxynucleotide (dNTP) triphosphohydrolase that has been recently linked to tumour initiation and development, although with controversial findings, either being recognized as a tumour suppressor in haematological cancers (9,10) or tumour promoting in several solid tumours, including ovarian cancer (11). On the other hand, mutations in SAMHD1 are linked to a severe congenital autoinflammatory disease known as Aicardi-Goutières syndrome (AGS) characterized by a dysregulated interferon (IFN) signalling due to defects in self and nonself nucleic acids recognition (12).…”

Expression of SAMHD1 and its mutation on prognosis of colon cancer

“…IHC was performed routinely on all primary colon cancer samples, as previously described ( 26 , 27 ). All samples were fixed in 10% neutral buffered formalin at room temperature for 1 h and maintained at 4°C with 30% saccharose overnight.…”