SASH1 (SAM And SH3 Domain Containing 1)

Our findings demonstrated that SASH1 inhibits proliferation, migration, invasion, epithelial-mesenchymal transition, and promotes melanin synthesis through TGF-β1 signaling, while THBS1 counteracts the increase in TGF-β1 levels induced by SASH1 knockdown. We further showed that SASH1 suppresses TGF-β1 through its regulatory effect on THBS1, thereby inhibiting melanin metastasis and promoting melanin synthesis, which offers potential therapeutic insights into the modulation of TGF-β1.

By systematically integrating multi-platform transcriptomics, machine learning, and multi-dimensional validation, this study identifies SASH1 as a robust prognostic biomarker and a potential predictor of therapeutic response in HNSCC. The established multi-omics pipeline provides a meaningful framework for biomarker discovery and highlights SASH1 as a promising target for advancing precision medicine in HNSCC.

This unique dual role of SASH1 highlights its importance in melanocyte homeostasis and UV-induced pigmentation. Understanding the role of SASH1 in regulating pigmentation can help foster novel therapeutic approaches for these genodermatoses and related pigmentary anomalies, ultimately improving patient care and outcomes.

High consistency in clinicopathological features and genetic basis in these two SASH1-related pigmentary disorders suggests that SASH1 mutations cause multiple lentigines and dyschromatosis which might belong to a disease spectrum. Overall, it is expected the current study results could help enhance a more comprehensive understanding of SASH1-related pigmentary dermatoses.

We further evaluated the drug sensitivity of FLT3-mutant patients to 3 FDA-approved FLT3i, gilteritinib, midostaurin, and quizartinib, and observed heightened sensitivity in FLT3-mutant cohorts, accompanied by the activation of immune-related pathways in treatment-responsive groups. These biomarkers were consistently upregulated in favorable prognostic subgroups and demonstrated strong correlations with immune activation pathways. The identification of CD36, SASH1, and NIBAN2 as predictive biomarkers offers a novel toolset for stratifying FLT3i response and prognosis.

Next, through docking studies, with the support of AlphaFold2 structure predictions, we investigated if/how mutations in SASH1-Sam1 could affect binding to EphA2-Sam. Our study, apart from presenting a solid multistep research protocol to analyze structural consequences related to cancer-associated protein variants with the support of cutting-edge artificial intelligence tools, suggests a few mutations that could more likely modulate the interaction between SASH1-Sam1 and EphA2-Sam.

Therefore, this study provides preliminary evidence that gastric cancer-derived exosomal miR-128-3p promotes tumour angiogenesis by targeting SASH1, reveals the potential diagnostic and therapeutic value of cancer-derived exosomal miR-128-3p, and provides new insights into the novel molecular mechanisms regulating metastasis. This study provides further information for understanding the role of gastric cancer-derived exosomal miR-128-3p in cancer progression and to discover new therapeutic targets.

Further experimental validation showed that SASH1 expression is significantly downregulated in breast cancer tissue (38.33%, 23/60), and the overexpression of SASH1 can inhibit the proliferation and invasion of breast cancer cells accompanied by the suppression of PI3K-Akt-mTOR signaling pathway. Additionally, SASH1 overexpression can improve OS and RFS of breast cancer patients.

Our findings reveal a novel MAP4K4-LATS2-SASH1-YAP1 phosphorylation cascade, a noncanonical Hippo pathway that mediates ER signaling, tumorigenesis and metastasis in breast cancer. Targeted intervention with this noncanonical Hippo pathway may constitute a novel alternative therapeutic approach for endocrine-resistant BC.

Clinically, LUAD patients with high expression of HMGB1 and low expression of SASH1 exhibited the worst clinical outcomes. Overall, the findings of this study revealed the critical role of HMGB1 in glycolysis and metastasis by attenuating H3K9ace and H3K27ace through physical interacted with SET and HAT1, which may facilitate future targeted therapies.

Moreover, injecting the human SASH1 mRNA rescued these phenomena in sash1a MO zebrafish. In summary, our study revealed that the downregulation of SASH1 leads to malformations in the embryonic brain and disorganization of glial cell marshalling, suggesting that SASH1 plays an important role in the migration of glial cells during embryonic brain development.

The dual-luciferase assay was used to determine the negative relationship between miR-4454 and its target genes, DNAJB4 and SASH1, and they were confirmed to be promising target genes of miR-4454. Taken together, this study suggests that the upregulation of miR-4454 derived from HERV-H in NMIBC reduces the expression of the tumor suppressor genes, DNAJB4 and SASH1, to promote NMIBC progression.