Abstract
Staphylococcal nuclease and tudor domain containing 1 (SND1) is a protein that regulates a complex array of functions. It controls gene expression through transcriptional activation, mRNA degradation, mRNA stabilization, ubiquitination and alternative splicing. More than two decades of research has accumulated evidence of the role of SND1 as an oncogene in various cancers. It is a promoter of cancer hallmarks like proliferation, invasion, migration, angiogenesis and metastasis. In addition to these functions, it has a role in lipid metabolism, inflammation and stress response. The participation of SND1 in such varied functions makes it distinct from most oncogenes that are relatively more focused in their role. This becomes important in the case of hepatocellular carcinoma (HCC) since in addition to typical cancer drivers, factors like lipid metabolism deregulation and chronic inflammation can predispose hepatocytes to HCC. The objective of this review is to provide a summary of the current knowledge available on SND1, specifically in relation to HCC and to shed light on its prospect as a therapeutic target.
Highlights
Hepatocellular carcinoma (HCC) is the primary liver malignancy arising from hepatocytes
Inhibition of Staphylococcal nuclease and tudor domain containing 1 (SND1) activity by pdTp abrogated LPS-induced nuclear translocation of p65 subunit of NF-κB and reduced the level of total p65[43]. This finding was observed in human HCC xenografts in nude mice that were treated with pdTp[43]. These findings suggest that as a transcriptional coactivator SND1 might be involved in regulating the expression of p65 itself, a hypothesis that needs to be interrogated
C-JNK phosphorylates SND1 at threonine 103, promoting the binding of its staphylococcal nuclease (SN) domain with GTPase activating protein SH3 domain binding protein (G3BP) to form stress granules[48]. It is not yet clear if the role of SND1 is limited to assembling these SGs or extends beyond that where the endonuclease activity of SND1 participates in degrading SG mRNAs
Summary
Hepatocellular carcinoma (HCC) is the primary liver malignancy arising from hepatocytes. SND1 is involved in regulating gene expression by transcriptional activation[18,19,20], alternative splicing[21], ubiquitination[17], mRNA stabilization[22] and RNA interference[23] These multifaceted properties allow SND1 to positively impact all hallmarks of cancer, notably sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis[24,25]. C-JNK phosphorylates SND1 at threonine 103, promoting the binding of its SN domain with G3BP to form stress granules[48] It is not yet clear if the role of SND1 is limited to assembling these SGs or extends beyond that where the endonuclease activity of SND1 participates in degrading SG mRNAs. Unfolded protein response or endoplasmic reticulum (ER) stress plays an important role in regulating NASH and NASH-induced HCC[49]. SND1 causes an increase in glycerolipid levels in cells by causing an increase in their synthesis or preventing their catabolism in hepatocytes [Figure 3]
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