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Chidambaranathan-Reghupaty et al. Hepatoma Res 2018;4:32 I http://dx.doi.org/10.20517/2394-5079.2018.34 Page 7 of 10

Figure 3. Possible role of SND1 in lipid metabolism. Exposure of human HCC cells to cholesterol-lowering drug or a lipoprotein-deficient
medium triggers SREBP2 activation and increases SND1 promoter activity. Studies in rat hepatoma cells show that SND1 overexpression
accumulates de novo synthesized cholesteryl esters. SND1 is induced by TNFα and subsequent profiling in human hepatoma cells
revealed that SND1 binds to the promoter regions of a group of glycerolipid metabolic genes including CHPT1, LPGAT1, PTDSS1 and
LPIN1 involved in the biosynthesis of phophatidylcholine, phosphatidylglycerol, phosphatidylserine and triacylglycerol, respectively. As
yet functional consequence of SND1 binding to the promoter of these genes has not been studied. In human HCC cells SND1 interacts
with MGLL and results in ubiquitination and proteosomal degradation of MGLL. The increase in monoglyceride (MG) levels is predicted
from the known role of MGLL. Studies in mouse adipocytes have shown that SND1 is a co-activator of PPARγ in adipogenesis. SND1:
staphylococcal nuclease and tudor domain containing 1; HCC: hepatocellular carcinoma

that SND1 plays a role in regulating both inflammation and lipid metabolism, and also the hallmarks of
cancer by a variety of mechanisms, suggesting that targeting SND1 might be a viable option for HCC. This
notion is strengthened by the observation that Alb/SND1 mice develop spontaneous HCC, thus establishing
[43]
SND1 as a tumor driver . SND1 is the only eukaryotic protein with a tudor and SN domains and the
quaternary fold can be employed to obtain specific small molecule inhibitors, such as pdTp. The efficacy
of pdTp in inhibiting growth of HCC xenografts in vivo is exciting and promising. However, this inhibitor
is required in high doses to inhibit SND1 and inhibits only the nuclease function and not the nucleic acid
binding function. Thus, it is important to identify better analogs of pdTP and develop strategies that can
achieve complete inhibition of SND1. Recent success of hepatocyte-specific nanoparticle-delivered siRNA
targeting oncogenes in HCC opens up potential of such strategy to inhibit SND1. Genetic deletion studies in
vivo would provide a clue to the effects such inhibitors could produce. Further in-depth studies using in vitro
and in vivo models are required to better understand the functional attributes of this pleiotropic molecule so
that it is efficiently targeted.

DECLARATIONS
Authors’ contributions
Wrote the manuscript: Chidambaranathan-Reghupaty S, Sarkar D
Edited the manuscript: Mendoza R, Fisher PB

Availability of data and materials
Not applicable.

Financial support and sponsorship
The present study was supported in part by The National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) Grant 1R01DK107451-01A1 (D. Sarkar).