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Page 2 of 10 Chidambaranathan-Reghupaty et al. Hepatoma Res 2018;4:32 I http://dx.doi.org/10.20517/2394-5079.2018.34

[1]
(NASH) . Treatment options are restricted to liver transplantation, surgical resection and ablation.
Chemotherapy for HCC is not very promising. HCC incidence has almost tripled since the 1980s and it is the
[2]
fastest rising cause of cancer related deaths in the US . Increase in rates of obesity and non-alcoholic fatty
liver disease (NAFLD) is an important factor for this trend.

HCC is usually diagnosed at advanced stages. Unfortunately, patients with advanced HCC do not have the
option of treatments like liver transplant or surgical resection since the liver is damaged beyond rescue at
this stage. Advanced HCC is also resistant to standard chemo- and radiotherapy. Sorafenib, regorafenib
and nivolumab are the three FDA approved chemotherapy drugs for advanced HCC. The multi-kinase
inhibitor sorafenib was approved in 2007 and the SHARP trial showed that it increases overall survival
[3]
of HCC patients from 7.9 to 10.7 months . Regorafenib, a sorafenib analog, was approved in 2016 and
[4]
increases overall survival from 7.8 to 10.6 months . Nivolumab, an immune oncology agent that blocks
programmed cell death 1 (PD1), a negative regulator of T-cell activation and response, thus allowing the
immune system to attack the tumor, was approved in 2017 for patients who have been previously treated
[5]
with sorafenib contingent on a successful phase III trial . Most of these drugs are expensive, effective in
only a small percentage of treated patients, cause side effects and do not provide a promising increase in
[7]
[6]
survival . Nivolumab increases overall survival to 13.2 months and has a more durable response . But, it is
administered intravenously every two weeks and has the same demerits as the other chemotherapy drugs.
The limitations of the current available treatment options mandate identification of new regulators of HCC
that might be targeted to develop effective therapy.

STAPHYLOCOCCAL NUCLEASE AND TUDOR DOMAIN CONTAINING 1: A MULTIFUNCTIONAL
ONCOGENE
Structure and activation
Human staphylococcal nuclease and tudor domain containing 1 (SND1) gene is located at chromosome
7q31.3 and codes for a protein of 910 amino acids with five highly conserved domains. It has a tandem repeat
of four staphylococcal nuclease (SN) domains and a fifth fusion domain of a tudor and a partial SN domain
[Figure 1A]. SND1 was first identified as a transcription co-activator that interacts with Epstein-Barr nuclear
[8]
antigen 2 (EBNA2) in lymphocytes . It acts as a bridge between the subunits p56 and p34 of the general
[9]
transcription factor TFIIE and the acidic domain of EBNA2 . SND1 is an evolutionarily conserved protein
in all eukaryotes from protozoa to humans except budding yeast saccharomyces cerevisiae [10-12] . The upstream
regulators of SND1 include the transcription factors NF-κB, NF-Y, Sp1 and SREBP-2 [Figure 1B]. A CpG
island with several Sp1 binding sites and an inverted CCAAT box binding to NF-Y regulate basal expression
of SND1 [13-15] . NF-κB binding site is located within the proximal 300 bp segment of SND1 promoter and
[13]
confers TNFα-mediated induction of SND1 [Figure 1B]. SREBP-2 binds to a proximal promoter region
containing a serum response element and an enhancer box motif and induces SND1 expression upon
[16]
cholesterol depletion . Activated Smad2 and Smad3 bind to SND1 promoter and confer TGFβ-medicated
[17]
induction of SND1 expression [Figure 1B].
Multifaceted properties
Staphylococcal nuclease protects bacteria from invading viruses by degrading viral nucleic acids. In higher
organisms, repeats of SN domains and the addition of the tudor domain has created a multifunctional
protein in SND1 especially with its ability to interact with a diverse array of proteins. SND1 is involved in
[21]
[17]
regulating gene expression by transcriptional activation [18-20] , alternative splicing , ubiquitination , mRNA
[22]
[23]
stabilization and RNA interference . 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] .