SAMHD1 is down regulated in lung cancer by methylation and inhibits tumor cell proliferation

Wang, Jia-lei; Lu, Fei; Shen, Xiaoyong; Wu, Yun; Zhao, Laiping

doi:10.1016/j.bbrc.2014.10.153

Cited by 59 publications

(87 citation statements)

References 24 publications

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“…protein and RNA expression of SAMHD1 has been observed, presumably caused by promoter methylations (30,33,34). However, it is unknown whether SAMHD1 somatic mutations found in cancers affect its dNTPase activity (35).…”

Section: Significancementioning

confidence: 99%

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Rentoft

Lindell

Tran

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

102

152

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Even small variations in dNTP concentrations decrease DNA replication fidelity, and this observation prompted us to analyze genomic cancer data for mutations in enzymes involved in dNTP metabolism. We found that sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1), a deoxyribonucleoside triphosphate triphosphohydrolase that decreases dNTP pools, is frequently mutated in colon cancers, that these mutations negatively affect SAMHD1 activity, and that several SAMHD1 mutations are found in tumors with defective mismatch repair. We show that minor changes in dNTP pools in combination with inactivated mismatch repair dramatically increase mutation rates. Determination of dNTP pools in mouse embryos revealed that inactivation of one SAMHD1 allele is sufficient to elevate dNTP pools. These observations suggest that heterozygous cancer-associated SAMHD1 mutations increase mutation rates in cancer cells.

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Section: Significancementioning

confidence: 99%

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Rentoft

Lindell

Tran

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

102

152

View full text Add to dashboard Cite

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“…Decreased nuclease expression could result in higher mutation rates and the accumulation of genotypes favoring cancer proliferation. Previously, only SAMHD1 downregulation has been reported in lung cancer [13] . The results of our colorectal cancer study have extended this observation to other nucleases.…”

Section: Tcga-aa-3511mentioning

confidence: 99%

“…Downregulation of gamma-inducible protein 16 (IFI16) and SAMHD1 has been reported in prostate cancer and lung adenocarcinoma, respectively [12,13] . SAMHD1 mutation has been shown to be oncogenic in chronic lymphocytic leukemia pathogenesis [14] .…”

mentioning

confidence: 99%

DNA-Sensing and Nuclease Gene Expressions as Markers for Colorectal Cancer Progression

Yang¹,

Huang

Chang

et al. 2016

Oncology

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Objective: Oncogene-driven stress-related DNA damage has been observed in lesions of colon cancer. Furthermore, DNA sensors and nucleases are stimulated during active DNA damage and replication. However, their changes and influences with respect to cancer remain largely unknown. Methods: The gene expression levels of cGAS, IFI16, STING, TBK1, IFNB1, TREX1, SAMHD1, RNASEH2A, RNASEH2B, and RNASEH2C were examined in the paired colorectal cancer and adjacent normal part tissues of 53 patients. Their associations with the clinical stages of cancer were then analyzed. Results: All cytosolic DNA-sensing and nuclease-related genes except cGAS, RNASEH2A, and RNASEH2B showed lower mRNA expressions in the colorectal tumor tissues. Moreover, cGAS upregulation was found to be associated with early-stage colorectal cancers, while higher expressions of RNASEH2B, RNASEH2C, and SAMHD1 correlated with metastasis. RNASEH2C knockdown in a colon cancer cell line impaired cell migration, and analysis of the cancer RNA-seq data from The Cancer Genome Atlas (TCGA) database revealed a negative correlation between RNASEH2C expression and E-cadherin levels. Conclusions: In contrast to DNA-sensing events in viral infections or autoimmunity, cGAS-STING-IFNB signaling is disrupted in colorectal cancer. The expression levels of cGAS, RNASEH2B, RNASEH2C, and SAMHD1 could be prognostic markers of colorectal cancer.

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“…Additionally, an imbalance to dNTP pools can lead to loss of genomic fidelity and impaired replication efficiency and accuracy (27–29, 199). It is therefore no surprise that recent studies have begun to implicate SAMHD1 in various cancers, including lymphocytic leukemia, lung adenocarcinoma, and colon cancer (106, 200–202) (Fig. 5).…”

Section: Samhd1 Mutations Results In Diseasementioning

confidence: 99%

“…Regulation of SAMHD1 begins at the transcriptional level, as several studies have demonstrated that the SAMHD1 promoter can be silenced by methylation (104–106). Two naturally occurring splice variants of SAMDH1 have been identified, consisting of truncated versions of the full-length protein (107).…”

Section: Samhd1 Cellular Regulation and Nucleotide Metabolismmentioning

confidence: 99%

SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity

Mauney

Hollis

2018

Autoimmunity

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SAMHD1 is a deoxynucleotide triphosphate (dNTP) hydrolase that plays an important role in the homeostatic balance of cellular dNTPs. Its emerging role as an effector of innate immunity is affirmed by mutations in the SAMHD1 gene that cause the severe autoimmune disease, Aicardi-Goutieres syndrome (AGS) and that are linked to cancer. Additionally, SAMHD1 functions as a restriction factor for retroviruses such as HIV. Here we review the current biochemical and biological properties of the enzyme including its structure, activity, and regulation by post-translational modifications in the context of its cellular function. We outline open questions regarding the biology of SAMHD1 whose answers will be important for understanding its function as a regulator of cell cycle progression, genomic integrity, and in autoimmunity.

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SAMHD1 is down regulated in lung cancer by methylation and inhibits tumor cell proliferation

Cited by 59 publications

References 24 publications

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

DNA-Sensing and Nuclease Gene Expressions as Markers for Colorectal Cancer Progression

SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity

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