<p>SASH1 Suppresses the Proliferation and Invasion of Human Skin Squamous Cell Carcinoma Cells via Inhibiting Akt Cascade</p>

Abstract

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. Methods: 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. Results: 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. Conclusion: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.

miR‐9 modulates and predicts the response to radiotherapy and EGFR inhibition in HNSCC

“…To explain how miR-9 may possibly regulate the tumorigenic potential of HNSCC cells, we first looked to the oncosuppressor SASH1 that we previously showed to be a bona fide miR-9 target in HNSCC (Citron et al, 2017) and has been involved in the regulation of EMT in different tumor types, including cutaneous SCC (He et al, 2016;Chen et al, 2020;Franke et al, 2020). As expected, modulation of miR-9 resulted in altered SASH1 protein expression (Figs 1B and EV1B and Appendix Fig S2B ,G,K).…”

Complement factor I upregulates expression of matrix metalloproteinase‐13 and ‐2 and promotes invasion of cutaneous squamous carcinoma cells

“…44,45 Accordingly, upregulation of MMP-2 expression is associated with tumor invasion in cSCC. 46 MMP-2 can also activate latent MMP-13, and may this way promote invasion of cSCC. 47 Interestingly, elevated expression of CFI has also been noted in other invasive cancers, including glioblastoma, pancreatic adenocarcinoma and stomach adenocarcinoma.…”

The emerging and diverse roles of the SLy/SASH1‐protein family in health and disease—Overview of three multifunctional proteins

“…Moreover, SASH1 was found to be cleaved directly by caspase‐3, and a resulting large C‐terminal cleavage product of SASH1 was reported to translocate into the nucleus where it is proposed to activate NFκB and eventually apoptosis 97 . Conversely, SASH1 downregulation increases cell proliferation in human skin squamous cell carcinoma cells 98 . The upregulation of SASH1 was also seen in apoptosis induced through external stimuli, such as treatment with chemicals like chloropyramine and 4‐hydroxytamoxifen, whereas UV irradiation of breast cancer cells induces cleavage and nuclear translocation of SASH1 99,100 .…”

“…97 Conversely, SASH1 downregulation increases cell proliferation in human skin squamous cell carcinoma cells. 98 The upregulation of SASH1 was also seen in apoptosis induced through external stimuli, such as treatment with chemicals like chloropyramine and 4-hydroxytamoxifen, whereas UV irradiation of breast cancer cells induces cleavage and nuclear translocation of SASH1. 99,100 However, the contribution of SASH1-related cell apoptosis to tumor suppression is still controversial.…”

“…One study refers to the influence of SASH1 on Akt signaling as an mechanistic approach to tumor suppression and shows a negative correlation of SASH1 overexpression and Akt suppression. 98 The exact mechanisms behind these observations still remain unclear, although different approaches and findings are discussed, including a higher number and migration of melanocytes and increased epidermal cell proliferation. As a model for these complex processes in pigmentation and melanocyte biology, melanoma cell lines such as A375 cells were used to investigate these mechanisms.…”