Recent studies have shown that metal and metal oxide have a potential function in anti-tumor therapy. Our previous studies demonstrated that cuprous oxide nanoparticles (CONPs) not only selectively induce apoptosis of tumor cells in vitro but also inhibit the growth and metastasis of melanoma by targeting mitochondria with little hepatic and renal toxicities in mice. As a further study, our current research revealed that CONPs induced apoptosis of human melanoma stem cells (CD271^+/high cells) in A375 and WM266-4 melanoma cell lines and could significantly suppress the expression of MITF, SOX10 and CD271 involved in the stemness maintenance and tumorigenesis of melanoma stem cells. CD271^+/high cells could accumulate more CONPs than CD271^-/low through clathrin-mediated endocytosis. In addition, lower dosage of CONPs exhibited good anti-melanoma effect by decreasing the cell viability, stemness and tumorigenesis of A375 and WM266-4 cells through reducing the expression of SOX10, MITF, CD271 and genes in MAPK pathway involved in tumor progression. Finally, CONPs obviously suppressed the growth of human melanoma in tumor-bearing nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice, accompanied with tumors structural necrosis and fibrosis remarkably and decreased expression of CD271, SOX10 and MITF. These results above proved the effectiveness of CONPs in inhibiting melanoma progress through multiple pathways, especially through targeting melanoma stem cells.

Background: Previous studies have shown that in myogenic precursors, the homeoprotein Msx1 and its protein partners, histone methyltransferases and repressive histone marks, tend to be enriched on target myogenic regulatory genes at the nuclear periphery. The nuclear periphery localization of Msx1 and its protein partners is required for Msx1’s function of preventing myogenic precursors from pre-maturation through repressing target myogenic regulatory genes. However, the mechanisms underlying the maintenance of Msx1 and its protein partners’ nuclear periphery localization are unknown. Results: We show that an inner nuclear membrane protein, Emerin, performs as an anchor settled at the inner nuclear membrane to keep Msx1 and its protein partners Ezh2, H3K27me3 enriching at the nuclear periphery, and participates in inhibition of myogenesis mediated by Msx1. Msx1 interacts with Emerin both in C2C12 myoblasts and mouse developing limbs, which is the prerequisite for Emerin mediating the precise location of Msx1, Ezh2, and H3K27me3. The deficiency of Emerin in C2C12 myoblasts disturbs the nuclear periphery localization of Msx1, Ezh2, and H3K27me3, directly indicating Emerin functioning as an anchor. Furthermore, Emerin cooperates with Msx1 to repress target myogenic regulatory genes, and assists Msx1 with inhibition of myogenesis. Conclusions: Emerin cooperates with Msx1 to inhibit myogenesis through maintaining the nuclear periphery localization of Msx1 and Msx1’s protein partners.

Although most prostate tumors are relatively indolent, advanced disease can progress to aggressive, often lethal variants, including neuroendocrine prostate cancer (NEPC). To identify drivers of aggressive prostate cancer, we used Sleeping Beauty (SB) transposon mutagenesis in a mouse model having prostate-specific loss of Pten and Tp53 (NPp53 mice). Compared with control NPp53-SB(−) mice, experimental NPp53-SB(+) mice developed more aggressive tumors with increased metastasis. Notably, NPp53-SB(+) mice exhibited NEPC phenotypes with transcriptomic features that recapitulate human NEPC. Analysis of recurrent common insertion sites (CIS) and associated genes (CIS genes) identified genes differentially expressed between NEPC and non-NEPC tumors. Analysis of NEPC-enriched CIS genes by cross-species integration of genomic and transcriptomic data prioritized sirtuin 1 (Sirt1) as a candidate mechanistic determinant of NEPC. Gain- and loss-of-function studies in human prostate cancer cells and mouse NEPC organoids confirmed that SIRT1 promotes NEPC, while pharmacological inhibition suppresses it. Thus, integration of cross-species analyses with an unbiased forward genetic screen uncovered novel drivers of NEPC.