Nischarin Deletion Reduces Oxidative Metabolism and Overall ATP: A Study Using a Novel NISCHΔ5-6 Knockout Mouse Model

Nguyen, Tina H.; Yousefi, Hassan; Okpechi, Samuel C.; Lauterboeck, Lothar; Dong, Shaohong; Yang, Qinglin

doi:10.3390/ijms23031374

Cited by 4 publications

(3 citation statements)

References 45 publications

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“…However, possible explanation for the differing prognostic role of NISCH in different cancer types may be attributed exactly to the NISCH association with cancer metabolism. NISCH has an important role in the maintenance of the cellular metabolic homeostasis [ 15 , 84 , 85 ], and activated NISCH has a role in caloric restriction in tissues [ 86 ]. Cancers are heterogeneous in their metabolic dependencies and preferred energy sources, and this is influenced by the anatomical location and the microenvironment.…”

Section: Discussionmentioning

confidence: 99%

“…When crossed with the MMTV-PyMT mice (a mouse strain in which the oncogenic polyoma virus middle T antigen is driven by the mouse mammary tumor virus promoter), NISCH mutant mice had increased breast tumor growth and metastasis [ 13 ]. They further developed a NISCH exon 5 and 6 knock-out mouse and showed that NISCH KO mouse embryonic fibroblasts had increased migration, but lower oxygen production rates and lower ATP production [ 14 ]. This confirmed that NISCH was involved in several biological processes important for cancer progression.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of the nischarin expression across human tumor types reveals its context-dependent role and a potential as a target for drug repurposing in oncology

Ostojić,

Đurić,

Živić

et al. 2024

PLoS ONE

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Nischarin was reported to be a tumor suppressor that plays a critical role in breast cancer initiation and progression, and a positive prognostic marker in breast, ovarian and lung cancers. Our group has found that nischarin had positive prognostic value in female melanoma patients, but negative in males. This opened up a question whether nischarin has tumor type-specific and sex-dependent roles in cancer progression. In this study, we systematically examined in the public databases the prognostic value of nischarin in solid tumors, regulation of its expression and associated signaling pathways. We also tested the effects of a nischarin agonist rilmenidine on cancer cell viability in vitro. Nischarin expression was decreased in tumors compared to the respective healthy tissues, most commonly due to the deletions of the nischarin gene and promoter methylation. Unlike in healthy tissues where it was located in the cytoplasm and at the membrane, in tumor tissues nischarin could also be observed in the nuclei, implying that nuclear translocation may also account for its cancer-specific role. Surprisingly, in several cancer types high nischarin expression was a negative prognostic marker. Gene set enrichment analysis showed that in tumors in which high nischarin expression was a negative prognostic marker, signaling pathways that regulate stemness were enriched. In concordance with the findings that nischarin expression was negatively associated with pathways that control cancer growth and progression, nischarin agonist rilmenidine decreased the viability of cancer cells in vitro. Taken together, our study lays a ground for functional studies of nischarin in a context-dependent manner and, given that nischarin has several clinically approved agonists, provides rationale for their repurposing, at least in tumors in which nischarin is predicted to be a positive prognostic marker.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Analysis of the nischarin expression across human tumor types reveals its context-dependent role and a potential as a target for drug repurposing in oncology

Ostojić,

Đurić,

Živić

et al. 2024

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…When crossed with the MMTV-PyMT mice NISCH mutant mice had increased breast tumor growth and metastasis (13). They further developed a NISCH exon 5 and 6 knock-out mouse and showed that NISCH KO mouse embryonic broblasts had increased migration, but lower oxygen production rates and lower ATP production (14). This con rmed that NISCH was involved in several biological processes important for cancer progression.…”

Section: Introductionmentioning

confidence: 96%

Pan-cancer analysis reveals that nischarin may not be the universal tumor suppressor

Ostojić

Đurić

Živić

et al. 2022

Preprint

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Background: Scaffolding protein nischarin (NISCH) was reported to be a tumor suppressor that plays a critical role in breast cancer initiation and progression through regulation of the cytoskeleton dynamics. NISCH expression was reported to be a positive prognostic marker in breast, ovarian and lung cancers. Our group has found that in melanoma, NISCH had positive prognostic value in female patients, but negative in males. These findings opened up a question whether NISCH has tumor type-specific and sex-dependent roles in cancer progression. Results: In this study, we systematically examined in the public databases the prognostic value of NISCH in solid tumors, regulation of its expression and associated signaling pathways with the special emphasis on the possible differences between male and female cancer patients. We found that NISCH expression was decreased in tumor compared to the respective healthy tissues, and that this was most commonly due to the deletions of the NISCH gene and promoter methylation. We also report that, unlike in healthy tissues where it was located in the cytoplasm and at the membrane, NISCH could be observed in the nuclei in tumor tissues. Surprisingly, we found that in many cancer types – colon, liver, skin, ovarian, prostate, and kidney – high NISCH expression was a negative prognostic marker. Gene set enrichment analysis showed that, while there were common pathways associated with NISCH expression in all the examined cancer types, in tumors in which high NISCHexpression was a negative prognostic marker Wnt-Notch-Hedgehog signaling gene networks were enriched. Conclusions: Our study questions the current tumor suppressor status of nischarin and lays a ground for functional studies in a context-dependent manner in cancer.

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Nischarin expression may have differing roles in male and female melanoma patients

et al. 2023

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Due to the development of resistance to previously effective therapies, there is a constant need for novel treatment modalities for metastatic melanoma. Nischarin (NISCH) is a druggable scaffolding protein reported as a tumor suppressor and a positive prognostic marker in breast and ovarian cancers through regulation of cancer cell survival, motility and invasion. The aim of this study was to examine the expression and potential role of nischarin in melanoma. We found that nischarin expression was decreased in melanoma tissues compared to the uninvolved skin, and this was attributed to the presence of microdeletions and hyper-methylation of the NISCH promoter in the tumor tissue. In addition to the previously reported cytoplasmic and membranous localization, we observed nischarin in the nuclei in melanoma patients' tissues. NISCH expression in primary melanoma had favorable prognostic value for female patients, but, unexpectedly, high NISCH expression predicted worse prognosis for males. Gene set enrichment analysis suggested signi cant sex-related disparities in predicted association of NISCH with several signaling pathways, as well as with different tumor immune in ltrate composition in male and female patients. Taken together, our results imply that nischarin may have a role in melanoma progression, but that ne-tuning of the pathways it regulates is sex-dependent.

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Nischarin Deletion Reduces Oxidative Metabolism and Overall ATP: A Study Using a Novel NISCHΔ5-6 Knockout Mouse Model

Cited by 4 publications

References 45 publications

Analysis of the nischarin expression across human tumor types reveals its context-dependent role and a potential as a target for drug repurposing in oncology

Analysis of the nischarin expression across human tumor types reveals its context-dependent role and a potential as a target for drug repurposing in oncology

Pan-cancer analysis reveals that nischarin may not be the universal tumor suppressor

Nischarin expression may have differing roles in male and female melanoma patients

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