SOX18 Inhibitor Improves Survival in Breast Cancer Mouse Models
Interference with transcription factor activity may lead to the development of novel disease therapeutics.
Targeting the SOX18 transcription factor significantly improved survival in mouse models of breast cancer, according to a study published in eLife.
Recent studies show that high levels of SOX18 are associated with a poor prognosis for cancer. The investigators hypothesized that pharmacological inhibition of SOX18 protein function may have the potential to manage the vascular response in cancer.
For the study, investigators mapped the SOX18 interactome by using a combination of unbiased proteomic technologies.
“Chromatin immunoprecipitation coupled to mass spectrometry (ChIP-MS) provided a first-pass screen for proteins associated with chromatin-bound SOX18 in human umbilical vein endothelial cells (HUVECs), then, ALPHA-Screen resolved SOX18-dependent complexes into pairwise interactions using in vitro translated full-length proteins,” the authors wrote.
Through the ChIP-MS analysis, investigators identified 289 proteins associated directly or indirectly with SOX18. The primary focus for the study was on proteins known to be nucleic acid or protein binding, to increase the chances of identifying direct interactors.
Eight known transcription factors, helicases, co-repressors, RNA binding, and DNA-repair molecules were chosen. The ALPHA-Screen allowed the investigators to observe SOX18 interacting with itself, and also form pairwise interactions with DDX1, DDX17, ILF3, STAT1, TRIM28, and XRCC5.
The investigators also examined the potential pairwise interactions of 6 well-known transcription factors that can regulate endothelial cell function, and the SOX18 protein partner MEF2C.
A combination of genomic, proteomic, and biophysical methods were used to discover a suite of protein-protein interactions that involved the SOX18 transcription factor—–a known regulator of vascular development and disease, according to the investigators.
Overall, the cumulative SOX18 peak-to-TSS distance showed that SOX18 peaks at 3.6-fold closer to the TSS of Sm4 down-regulated genes compared with randomly distributed TSSs. The results show an indirect indication that the Sm4 affects genes are dysregulated through a specific effect on SOX18 transcription activity, according to the authors. However, the correlation was not found for 7 of the transcription factors tested.
The results of the study showed that Sm4—–a small molecule that disrupts of SOX18-dependent interactions. The compound was able to selectively suppress SOX18 transcriptional outputs in vitro and interfered with vascular development in zebrafish larvae.
In mouse models of breast cancer, the investigators found that treatment with a SOX18 inhibitor significantly improved survival, and reduced the vascular density of tumors as well as metastasis.
“Our studies validate an interactome-based molecular strategy to interfere with transcription factor activity, for the development of novel disease therapeutics,” the authors concluded.