Commentary

490428524
Title of commentary: Sm4 the answer to regulating SOX18 activity?

Commentary on: Overman, J., Fontaine, F., Moustaqil, M., Mittal, D., Sierecki, E., Sacilotto,
N., Zuegg, J., Robertson, A., Holmes, K., Salim, A., Mamidyala, S., Butler, M., Robinson, A.,
Lesieur, E., Johnston, W., Alexandrov, K., Black, B., Hogan, B., De Val, S., Capon, R., Carroll, J.,
Bailey, T., Koopman, P., Jauch, R., Smyth, M., Cooper, M., Gambin, Y. and Francois, M. 2017,
Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice,
eLife, vol 6,.
Implications for future research/application
- Sm4 interferes with SOX18 protein-protein interactions on a genome-wide scale,
downregulating expression of genes involved in the development of blood vessels
and lymphatic vasculature.
- Sm4 as a potential new treatment for cancer patients, to reduce tumour spread and
growth. The study opens the door for clinical trials utilising Sm4 as a cancer therapy.
- Sm4 is selective for SOX18 transcription factors and does not affect other
transcription factors
Context/Background
SOX18 is a transcription factor apart of the SOXF group, which plays a vital role in regulating
the development of blood and lymphatic vessels (Downes, 2001). Suppression of SOX18 has
been shown to inhibit tumour growth and metastasis (Duong et al., 2014), by preventing the
formation of blood and lymphatic vessels that aid tumour spread and growth. Previous
studies have shown that those patients with a higher presence of SOX in their system had a
poorer outcome for their cancer (Olbromski et al., 2017). The current study sought to test
whether the small molecular compound, Sm4, created from brown alga Caulocystis
cephalornithos, could successfully interfere with SOX18 activity and hence reduce tumour
growth and metastasis. This is of high importance for the development of new cancer
therapies that produce better outcomes for patient’s longevity and health (Olbromski et al.,
2017). Previous studies have accentuated the difficulty in targeting transcription factors,
and successfully inhibiting their function, considering the redundancy mechanism which are
in place to rescue the loss of TFs (Watkins, 2009). SOX18 transcription factors are embedded
as a node within a network of protein-protein interactions, disruption of this network has
been posited as a method to inhibit the SOX18. Thereby, the current study offers a new
strategy to attack the interactome of SOX18, in order to successfully inhibit its activity and
create useful cancer therapeutics.
Methods
The objectives of the paper were to test whether Sm4 was able to interfere with SOX18
activity and reduce tumour growth and metastasis. The methodology was very well
described, with additional details on methods used included at the end of paper. The
proteins in the interactome of SOX18 complex were detected through the primary
combined analysis of chromatin immunoprecipitation and mass spectrometry. Once
identified, these interacting proteins were then put through an ALPHA-Screen to validate
whether they were direct protein-protein interactions (PPIs) in the SOX18 complex. Thereby,
providing a thorough analysis of the PPIs that define the interactome of the SOX18 complex.
Genome-wide RNA-sequencing and ChIP-sequencing analysis were conducted on human
umbilical vein endothelium cells. The study was able to determine whether transcription
would be regulated by contrasting the distance from the transcription start site and
transcription binding site of Sm4 and other non-affected genes (indicated by peak in ChIP-
seq). Assays were utilised effectively throughout the research to measure activity of SOX18.
Main results/findings
The current research illuminated the SOX18 interactome. Sm4 was found to disrupt six of
the twelve SOX-18 interactions, including DDX17, ILF3, SOX18, XRCC5, RBPJ, SOX7. In vitro,
Sm4 was found to be selective in regard to its effect on the result of transcription promoted
by SOX18. In vivo, Sm4 was also found to interfere with SOX18-related transcription
products in zebrafish larvae and inhibit tumour size and spread in a mouse model.
Commentary:
The current paper’s research offers a heightened insight into the potential to modulate the
activity of the SOX18 transcription factor, and consequently inhibit the expression of blood
and lymphatic vasculature. The study offers new and exciting avenues to control genetic
expression, with far-reaching and favourable outcomes for treating cancer patients to
control tumour metastasis and growth and increase survival.
The function of SOX18 as a transcription factor is vital to the development of lymphatic and
blood vasculature. The ability to target SOX18, through the use of the small molecular
inhibitor; Sm4 presents a ground-breaking scientific discovery, that unlocks far-reaching
potential to transform the therapeutic approach to cancer. The mapping of the SOX18
interactome highlights the necessity for Sm4 to sufficiently disrupt the PPIs of SOX18 in
order to successfully inhibit transcription resulting in angiogenesis and lymphangiogenesis.
The study highlighted that Sm4 is able to disrupt six of the twelve SOX18 interactions.
However, additional research should be conducted to further elucidate other potential PPIs
involved in the SOX18 complex. Nevertheless, the study highlighted that this PPI disruption
is sufficient to translate into transcriptional dysregulation. This PPI disruption causes SOX18
to be unable to recruit its specific interacting partners and hence prevents the genetic
expression of vascular angiogenesis and lymphangiogenesis. (Sarkar and Hochedlinger,
2013). This revolutionary insight into the ability of Sm4 to downregulate SOX18 activity was
strongly support in the paper through in vivo experimentation.
Altogether, this comprehensive study highlights the potential for the small molecule Sm4 to
interfere with SOX18 protein-protein interactions. Offering ground-breaking progress
towards the development of SOX18 small-molecule inhibitor, that is able to act on the
network of protein-protein interactions to inhibit SOX18 activity. Thereby, the current study
offers a revolutionary strategy to attack the interactome of SOX18, which has far-reaching
potential for cancer-therapy. However, the future of Sm4 to inhibit SOX18 activity and
become a reliable cancer therapy to control tumour growth and metastasis is reliant on
clinical trialling to test the actual effectiveness of Sm4 in patients.
References
Downes, M. 2001, SOX18 and the Transcriptional Regulation of Blood Vessel Development,
Trends in Cardiovascular Medicine, vol 11, no 8, pp.318-324,.
Duong, T., Koltowska, K., Pichol-Thievend, C., Le Guen, L., Fontaine, F., Smith, K., Truong, V.,
Skoczylas, R., Stacker, S., Achen, M., Koopman, P., Hogan, B. and Francois, M. 2014, VEGFD
regulates blood vascular development by modulating SOX18 activity, Blood, vol 123, no 7,
pp.1102-1112,.
Olbromski, M., Rzechonek, A., Grzegrzolka, J., Glatzel-Plucinska, N., Chachaj, A., Werynska,
B., Podhorska-Okolow, M. and Dziegiel, P. 2017, Influence of miR-7a and miR-24-3p on the
SOX18 transcript in lung adenocarcinoma, Oncology Reports,.
Sarkar, A. and Hochedlinger, K. 2013, The Sox Family of Transcription Factors: Versatile
Regulators of Stem and Progenitor Cell Fate, Cell Stem Cell, vol 12, no 1, pp.15-30,.
Watkins, M. 2009, Sox18 induces development of the lymphatic vasculature in

mice, Yearbook of Vascular Surgery, vol 2009, pp.27-28,.

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490428524

Title of commentary: Sm4 the answer to regulating SOX18 activity?

Watkins, M. 2009, Sox18 induces development of the lymphatic vasculature in

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