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Figure 1. Upstream regulators of SND1 and downstream molecules involved in SND1 activity. A: Structure of SND1 protein; B: schematic overview
of the upstream regulators of SND1 and downstream mediators of SND1 activity. Colored molecules indicate those that have been identified in
HCC studies. SN: staphylococcal nuclease domains; SND1: staphylococcal nuclease and tudor domain containing 1; HCC: hepatocellular carcinoma

Downstream regulators and oncogenic mechanisms
SND1 interacts with and functions as a co-activator for a number of transcription factors that include
[19]
signal transducer and activator of transcription 5 (STAT5) , STAT6 [19,26] , peroxisome proliferator activated
[20]
[27]
receptor gamma (PPARγ) and c-Myb . It functions as a co-activator for the transcription factor E2F-1
[28]
facilitating G1/S phase transition . SND1 induces the E3 ubiquitin ligase Smurf1 resulting in ubiquitination
[17]
and degradation of RhoA and promotion of invasion, migration and metastasis . SND1 interacts with the
U5 spliceosomal RNA to assemble the spliceosome, affecting the levels of various splice variants, such as
generation of a variable form of CD44 that promotes motility and invasiveness of prostate cancer cells [21,29] .
It is a subunit of the RNA-induced silencing complex (RISC) in caenorhabditis elegans, drosophila and
[23]
mammals and functions in miRNA-directed mRNA degradation . SND1 is also involved in mature
miRNA decay. Knocking out SND1 inhibits cell cycle progression by upregulating a cohort of miRNAs that
[30]
downregulate mRNAs encoding proteins critical for the G1/S phase transition . In parallel to degrading
[22]
mRNA or miRNA, SND1 shows the ability to bind to 3’-UTR of specific mRNA and increase its stability .
Transcriptional activation of oncogenes, over-expression of oncogenic splice variants through alternative
splicing, degradation of tumor suppressor proteins and silencing of tumor suppressor mRNAs are some
of the means used by SND1 to contribute to tumorigenesis [Figure 2]. Given its role in regulating a wide
variety of cellular properties, it comes as no surprise that SND1 functions as an oncogene in a variety of
[25]
cancers, including breast, liver, lung, gastric, glial, prostate and colorectal cancer . Although the molecular
mechanism by which SND1 is overexpressed in cancer is not clear, it has been identified as a target of a
[31]
number of tumor suppressor miRNAs, such as microRNA-320a in lung cancer , microRNA-361-5p in
[33]
[32]
colorectal and gastric cancer , and miRNA-184 in malignant glioma [Figure 1B]. SND1 can be activated
[34]
by TGF-β1 and in turn activate Smurf1 to promote breast cancer metastasis . An SND1-BRAF fusion
protein has been identified in gastric, pancreatic and lung cancers that results in activation of downstream
MAPK signaling and confers resistance to chemotherapeutic drugs [35-37] [Figure 1B].