Because of the association between aberrant nuclear structure and tumour grade, nuclear morphology is an indispensible criterion in the current pathological assessment of cancer. Components of the nuclear envelope environment have central roles in many aspects of cell function that affect tumour development and progression. As the roles of the nuclear envelope components, including nuclear pore complexes and nuclear lamina, are being deciphered in molecular detail there are opportunities to harness this knowledge for cancer therapeutics and biomarker development. In this Review, we summarize the progress that has been made in our understanding of the nuclear envelope and the implications of changes in this environment for cancer biology.
Glioma stem cells (GSCs) and epithelial-mesenchymal transition (EMT) are strongly associated with therapy resistance and tumor recurrence, but the underlying mechanisms are incompletely understood. Here we show that S100A4 is a novel biomarker of GSCs. S100A4+ cells in gliomas are enriched with cancer cells that have tumor-initiating and sphere-forming abilities, with the majority located in perivascular niches where GSCs are found. Selective ablation of S100A4-expressing cells was sufficient to block tumor growth in vitro and in vivo. We also identified S100A4 as a critical regulator of GSC self-renewal in mouse and patient-derived glioma tumorspheres. In contrast to previous reports of S100A4 as a reporter of EMT, we discovered that S100A4 is an upstream regulator of the master EMT regulators SNAIL2 and ZEB along with other mesenchymal transition regulators in glioblastoma. Overall, our results establish S100A4 as a central node in a molecular network that controls stemness and EMT in glioblastoma, suggesting S100A4 as a candidate therapeutic target.
Numerous enzymes of the mammalian SUMO modification pathway, including two members of the SUMO protease family, SENP2 and SENP1, localize to the nuclear periphery. The SUMO proteases play roles both in processing SUMO during the biogenesis of this peptide moiety and also in reversing SUMO modification on specific targets to control the activities conferred by this post-translational modification. Although interaction with the C-terminal domain of the nucleoporin Nup153 is thought to contribute to SENP2 localization at the nuclear pore complex, little is known about the binding partners of SENP1 at the nuclear periphery. We have found that Nup153 binds to both SENP1 and SENP2 and does so by interacting with the unique N-terminal domain of Nup153 as well as a specific region within the C-terminal FG-rich region. We have further found that Nup153 is a substrate for sumoylation, with this modification kept in check by these two SUMO proteases. Specifically, either RNAi depletion of SENP1/SENP2 or expression of dominantly interfering mutants of these proteins results in increased sumoylation of endogenous Nup153. While SENP1 and SENP2 share many characteristics, we show here that SENP1 levels are influenced by the presence of Nup153, whereas SENP2 is not sensitive to changes in Nup153 abundance.
Despite multimodal treatment that includes surgery, radiation and chemotherapy, virtually all glioblastomas (GBM) recur, indicating that these interventions are insufficient to eradicate all malignant cells. To identify potential new therapeutic targets in GBMs, we examined the expression and function of proteins that are associated with therapy resistance and cancer cell survival. We measured the expression of eight such proteins in 50 GBM samples by immunohistochemistry and analyzed patient survival. We report that GBM patients with high expression of ABCG2 (also called BCRP) or XIAP at the protein level had worse survival than those with low expression. The adjusted hazard ratio for ABCG2 was 2.35 and for XIAP was 2.65. Since glioma stem cells (GSCs) have been shown to be more resistant than bulk tumor cells to anti-cancer therapies and to express high levels of these proteins, we also sought to determine if ABCG2 and XIAP have functional roles in GSCs. We used small molecule inhibitors to treat patient-derived GBM tumorspheres in vitro and observed that inhibitors of ABCG2, Ko143 and fumitremorgin, significantly reduced self-renewal. These results suggest that ABCG2 and XIAP proteins may be useful indicators of patient survival and that inhibition of ABCG2 may be a promising therapeutic target in GBMs.
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