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Tankyrases, a versatile protein group within the poly(ADP-ribose) polymerase family, are essential for post-translational poly(ADP-ribosyl)ation, influencing various cellular functions and contributing to diseases, particularly cancer. Consequently, tankyrases have become important targets for anti-cancer drug development. Emerging approaches in drug discovery aim to disrupt interactions between tankyrases and their binding partners, which hinge on tankyrase-binding motifs (TBMs) within partner proteins and ankyrin repeat cluster domains within tankyrases. Our study addresses the challenge of identifying and ranking TBMs. We have conducted a comprehensive review of the existing literature, classifying TBMs into three distinct groups, each with its own scoring system. To facilitate this process, we introduce TBM Hunter—an accessible, web-based tool. This user-friendly platform provides a cost-free and efficient means to screen and assess potential TBMs within any given protein. TBM Hunter can handle individual proteins or lists of proteins simultaneously. Notably, our results demonstrate that TBM Hunter not only identifies known TBMs but also uncovers novel ones. In summary, our study offers an all-encompassing perspective on TBMs and presents an easy-to-use, precise, and free tool for identifying and evaluating potential TBMs in any protein, thereby enhancing research and drug development efforts focused on tankyrases.

SASH1 (SAM and SH3 domain containing 1) has been increasingly reported as a tumor suppressor gene. However, there is limited research on the role of SASH1 in breast cancer. This manuscript aims to investigate the mechanism of SASH1 in the occurrence, development, and prognosis of breast cancer. Firstly, we obtained RNA-sequencing data of the tumors from the Genomic Data Commons data portal website, along with the corresponding clinical information of patients. Pan-cancer analysis was performed to analyze the expression of SASH1 across all tumors. Univariate Cox regression analysis was used to assess the correlation between SASH1 expression and the prognosis of breast cancer patients. Then, immunohistochemistry was utilized to evaluate the expression levels of SASH1, p-Akt, p-PI3K, and p-mTOR in breast cancer tissue. Finally, a cell assay was employed to analyze the impact of SASH1 on the proliferation and invasion of breast cancer cells (MDA-MB-231). The results revealed that SASH1 expression is decreased in BRCA, LUSC, LUAD, CESC, ESCA, and COAD. Meta-analysis also found that SASH1 is downregulated in most tumor tissues, and the expression level of SASH1 in breast cancer was significantly lower than that in the control group (OR = 0.14, 95% CI = 0.08–0.25; P  < 0.001). 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.

Background: Sorafenib resistance remains a major barrier to effective therapy in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). Introduction: Here, we identified a previously undefined mechanism by which miR-21 promotes sorafenib resistance by suppressing the tumor suppressor SASH1 and enhancing HBx-driven PI3K/AKT/mTOR signaling. Methods: miR-21 expression was markedly elevated in HBV-HCC tissues, HBV-integrated HCC cell lines, and hypoxic conditions. Bioinformatic analyses and luciferase reporter assays confirmed SASH1 as a direct miR-21 target. Results: Mechanistically, SASH1 was functionally associated with HBx-related oncogenic signaling and influenced apoptotic responses. miR-21 inhibition reduced HBV-HCC cell proliferation, increased apoptosis, and restored sorafenib sensitivity in vitro. In an orthotopic HBV-HCC mouse model, the combined administration of miR-21 inhibitor and sorafenib elicited markedly greater tumor suppression and restoration of the SASH1 expression than either monotherapy did. Discussion: Therefore, these findings suggested that the miR-21/SASH1 pathway contributed to therapeutic resistance in HBV-associated HCC and highlighted that miR-21 targeting could be an efficient strategy to improve sorafenib response. Conclusions: The miR-21/SASH1 axis play a critical role in sorafenib resistance in HBV-associated HCC, and targeting miR-21 may provide a promising therapeutic strategy to enhance treatment efficacy.

Recently, SASH1 has emerged as a novel protein interactor of a few Eph tyrosine kinase receptors like EphA2. These interactions involve the first N-terminal Sam (sterile alpha motif) domain of SASH1 (SASH1-Sam1) and the Sam domain of Eph receptors. Currently, the functional meaning of the SASH1-Sam1/EphA2-Sam complex is unknown, but EphA2 is a well-established and crucial player in cancer onset and progression. Thus, herein, to investigate a possible correlation between the formation of the SASH1-Sam1/EphA2-Sam complex and EphA2 activity in cancer, cancer-linked mutations in SASH1-Sam1 were deeply analyzed. Our research plan relied first on searching the COSMIC database for cancer-related SASH1 variants carrying missense mutations in the Sam1 domain and then, through a variety of bioinformatic tools and molecular dynamic simulations, studying how these mutations could affect the stability of SASH1-Sam1 alone, leading eventually to a defective fold. 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.

SAM domains are crucial mediators of diverse interactions, including those important for tumorigenesis or metastasis of cancers, and thus SAM domains can be attractive targets for developing cancer therapies. This review aims to explore the literature, especially on the recent findings of the structural dynamics, regulation, and functions of SAM domains in proteins containing more than one SAM (multi-SAM containing proteins, MSCPs). The topics here include how intrinsic disorder of some SAMs and an additional SAM domain in MSCPs increase the complexity of their interactions and oligomerization arrangements. Many similarities exist among these MSCPs, including their effects on cancer cell adhesion, migration, and metastasis. In addition, they are all involved in some types of receptor-mediated signaling and neurology-related functions or diseases, although the specific receptors and functions vary. This review also provides a simple outline of methods for studying protein domains, which may help non-structural biologists to reach out and build new collaborations to study their favorite protein domains/regions. Overall, this review aims to provide representative examples of various scenarios that may provide clues to better understand the roles of SAM domains and MSCPs in cancer in general.

Aims This study aimed to evaluate the effects of the depletion of SAM and SH3 domain‐containing protein 1 (SASH1) on functional recovery after spinal cord injury (SCI) and to investigate the possible mechanism of SASH1 knockdown in astrocytes facilitating axonal growth. Methods SCI model was established in adult rats. SASH1 small interfering RNA (siSASH1) was used to investigate its function. Hindlimb motor function was evaluated by the Basso‐Bresnahan‐Beattie (BBB) assay. The gene expressions were evaluated by the methods of qRT‐PCR, Western‐blotting, ELISA, and immunohistochemistry. Results SASH1 knockdown improved the BBB scores after SCI and significantly reduced GFAP expression. In cultured spinal astrocytes, siSASH1 treatment decreased interferon‐γ release and increased brain‐derived neurotrophic factor (BDNF) release. When cocultured with SASH1‐knockdown astrocytes, axonal growth increased. The neuronal tropomyosin receptor kinase B (BDNF receptor) expression increased, especially in the axonal tips. SASH1 expression increased while NSCs differentiated into glial cells, instead of neurons. After SASH1 depletion, differentiated NSCs maintained a higher level of Nestin protein and an increase in BDNF release. Conclusions These results indicate that SASH1 acts as an astrocytic differentiation‐maintaining protein, and SASH1 downregulation limits glial activation and contributes toward functional recovery after SCI. SASH1 expression increased significantly during NSCs differentiation into glial cells and spinal cord injury (SCI). SASH1 knockdown in primary astrocytes increased the release of BDNF and promoted axonal growth; SASH1 knockdown significantly reduced astrocytes activation and improved the recovery of function after SCI.

The SAM- and SH3-domain containing 1 gene (SASH1) has been considered as a tumor suppressor in some cancers. Nevertheless, the effect of SASH1 on the proliferation and invasion of human skin squamous cell carcinoma (cSCC) remains poorly understood. Therefore, the purpose of the present study was to observe the potential role of SASH1 in cSCC and investigate its underlying mechanisms. The overexpression of SASH1 was constructed by transfecting the pcDNA3.1/SASH1 vector into SCL-1 and A431 cells, and SASH1 knockdown was generated by transfecting the SASH1 siRNA into cSCC cells. Then, cell proliferation, invasion, apoptosis, and Akt pathway were observed. The expression levels of SASH1 mRNA and protein were greatly reduced in cSCC cells. The overexpression of SASH1 inhibited the viability and invasion of cSCC cells, while its knockdown induced the viability and invasion of cSCC cells. The overexpression of SASH1 also suppressed the expression levels of p-Akt and its target genes, including cyclin D1, Bcl-2, and metal matrix proteinase 2(MMP-2). By contrast, SASH1 knockdown exerted the opposite role. Furthermore, inhibition of Akt obviously decreased the inducible effect of cSCC knockdown on the proliferation and invasion of cSCC cells. Overall, these results found that SASH1 inhibits the proliferation and invasion of cSCC cells via suppressing Akt cascade, indicating a tumor inhibitory effect of SASH1 in cSCC cells.

p53‐Transcriptional‐regulated proteins interact with a large number of other signal transduction pathways in the cell, and a number of positive and negative autoregulatory feedback loops act upon the p53 response. P53 directly controls the POMC/α‐MSH productions induced by ultraviolet (UV) and is associated with UV‐independent pathological pigmentation. When identifying the causative gene of dyschromatosis universalis hereditaria (DUH), we found three mutations encoding amino acid substitutions in the gene SAM and SH3 domain containing 1 (SASH1), and SASH1 was associated with guanine nucleotide‐binding protein subunit‐alpha isoforms short (Gαs). However, the pathological gene and pathological mechanism of DUH remain unknown for about 90 years. We demonstrate that SASH1 is physiologically induced by p53 upon UV stimulation and SASH and p53 is reciprocally induced at physiological and pathophysiological conditions. SASH1 is regulated by a novel p53/POMC/α‐MSH/Gαs/SASH1 cascade to mediate melanogenesis. A novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop is regulated by SASH1 mutations to induce pathological hyperpigmentation phenotype. Our study demonstrates that a novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop is regulated by SASH1 mutations to induce pathological hyperpigmentation phenotype.

Background Dyschromatosis universalis hereditaria (DUH) is a pigmentary dermatosis characterized by generalized mottled macules with hypopigmention and hyperpigmention. ABCB6 and SASH1 are recently reported pathogenic genes related to DUH, and the aim of this study was to identify the causative mutations in a Chinese family with DUH. Methods Sanger sequencing was performed to investigate the clinical manifestation and molecular genetic basis of these familial cases of DUH, bioinformatics tools and multiple sequence alignment were used to analyse the pathogenicity of mutations. Results A novel missense mutation, c.1529G>A, in the SASH1 gene was identified, and this mutation was not found in the National Center for Biotechnology Information Database of Short Genetic Variation, Online Mendelian Inheritance in Man, ClinVar, or 1000 Genomes Project databases. All in silico predictors suggested that the observed substitution mutation was deleterious. Furthermore, multiple sequence alignment of SASH1 revealed that the p.S510N mutation was highly conserved during evolution. In addition, we reviewed the previously reported DUH-related gene mutations in SASH1 and ABCB6 . Conclusion Although the affected family members had identical mutations, differences in the clinical manifestations of these family members were observed, which reveals the complexity of the phenotype-influencing factors in DUH. Our findings reveal the mutation responsible for DUH in this family and broaden the mutational spectrum of the SASH1 gene.