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SAT-144 Cooperative Mechanism of SREBP-Dependent Cholesterol Synthesis Pathway and P53 on Malignant Formation in Breast Cancer

p53 is mutated more than half of human cancers, and mutant p53, a gain of function, can actively have functional consequences with tumorigenesis. However, its action of molecular mechanisms, particularly in vivo conditions, has not been fully are clarified. Here, we generated KO and KI (R280K) breas...

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Autores principales: Nakayama, Akitoshi, Yokoyama, Masataka, Nagano, Hidekazu, Sakuma, Ikki, Hashimoto, Naoko, Higuchi, Seiichiro, Yamagata, Kazuyuki, Tanaka, Tomoaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207476/
http://dx.doi.org/10.1210/jendso/bvaa046.1670
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author Nakayama, Akitoshi
Yokoyama, Masataka
Nagano, Hidekazu
Sakuma, Ikki
Hashimoto, Naoko
Higuchi, Seiichiro
Yamagata, Kazuyuki
Tanaka, Tomoaki
author_facet Nakayama, Akitoshi
Yokoyama, Masataka
Nagano, Hidekazu
Sakuma, Ikki
Hashimoto, Naoko
Higuchi, Seiichiro
Yamagata, Kazuyuki
Tanaka, Tomoaki
author_sort Nakayama, Akitoshi
collection PubMed
description p53 is mutated more than half of human cancers, and mutant p53, a gain of function, can actively have functional consequences with tumorigenesis. However, its action of molecular mechanisms, particularly in vivo conditions, has not been fully are clarified. Here, we generated KO and KI (R280K) breast cancer cell lines for p53 using CRISPR/Cas9 system, and then performed a three-dimensional culture model. We found that the introduction of mutant p53 was solely able to mediate the transformation to poor architectural structure. Interestingly, our findings in statin-effect along with cholesterol synthesis pathway, especially isoprenoid dependency, revealed that this pathway is necessary and sufficient for the regulation of malignant architecture in SREBP2-dependent manner with cooperatively being controlled by mutant p53 on 3D-cultured breast cancer. Furthermore, in accordance with the malignancy progresses, SREBP2 was accumulated in nuclear and nuclear membrane portion with enhancement in malignant formation. In addition, we found that mutant p53 interacts with SREBP2, and consistently mutant p53 was associated with DHCR7 promoter in parallel with binding pattern of SREBP2. Thus, our results provide the novel insight into the mutant p53, a gain of function, and its linkage to poor architectural structure in 3D-cultured breast cancer cells via SREBP2-dependent isoprenoids regulation as potential therapeutic targets.
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spelling pubmed-72074762020-05-13 SAT-144 Cooperative Mechanism of SREBP-Dependent Cholesterol Synthesis Pathway and P53 on Malignant Formation in Breast Cancer Nakayama, Akitoshi Yokoyama, Masataka Nagano, Hidekazu Sakuma, Ikki Hashimoto, Naoko Higuchi, Seiichiro Yamagata, Kazuyuki Tanaka, Tomoaki J Endocr Soc Tumor Biology p53 is mutated more than half of human cancers, and mutant p53, a gain of function, can actively have functional consequences with tumorigenesis. However, its action of molecular mechanisms, particularly in vivo conditions, has not been fully are clarified. Here, we generated KO and KI (R280K) breast cancer cell lines for p53 using CRISPR/Cas9 system, and then performed a three-dimensional culture model. We found that the introduction of mutant p53 was solely able to mediate the transformation to poor architectural structure. Interestingly, our findings in statin-effect along with cholesterol synthesis pathway, especially isoprenoid dependency, revealed that this pathway is necessary and sufficient for the regulation of malignant architecture in SREBP2-dependent manner with cooperatively being controlled by mutant p53 on 3D-cultured breast cancer. Furthermore, in accordance with the malignancy progresses, SREBP2 was accumulated in nuclear and nuclear membrane portion with enhancement in malignant formation. In addition, we found that mutant p53 interacts with SREBP2, and consistently mutant p53 was associated with DHCR7 promoter in parallel with binding pattern of SREBP2. Thus, our results provide the novel insight into the mutant p53, a gain of function, and its linkage to poor architectural structure in 3D-cultured breast cancer cells via SREBP2-dependent isoprenoids regulation as potential therapeutic targets. Oxford University Press 2020-05-08 /pmc/articles/PMC7207476/ http://dx.doi.org/10.1210/jendso/bvaa046.1670 Text en © Endocrine Society 2020. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Tumor Biology
Nakayama, Akitoshi
Yokoyama, Masataka
Nagano, Hidekazu
Sakuma, Ikki
Hashimoto, Naoko
Higuchi, Seiichiro
Yamagata, Kazuyuki
Tanaka, Tomoaki
SAT-144 Cooperative Mechanism of SREBP-Dependent Cholesterol Synthesis Pathway and P53 on Malignant Formation in Breast Cancer
title SAT-144 Cooperative Mechanism of SREBP-Dependent Cholesterol Synthesis Pathway and P53 on Malignant Formation in Breast Cancer
title_full SAT-144 Cooperative Mechanism of SREBP-Dependent Cholesterol Synthesis Pathway and P53 on Malignant Formation in Breast Cancer
title_fullStr SAT-144 Cooperative Mechanism of SREBP-Dependent Cholesterol Synthesis Pathway and P53 on Malignant Formation in Breast Cancer
title_full_unstemmed SAT-144 Cooperative Mechanism of SREBP-Dependent Cholesterol Synthesis Pathway and P53 on Malignant Formation in Breast Cancer
title_short SAT-144 Cooperative Mechanism of SREBP-Dependent Cholesterol Synthesis Pathway and P53 on Malignant Formation in Breast Cancer
title_sort sat-144 cooperative mechanism of srebp-dependent cholesterol synthesis pathway and p53 on malignant formation in breast cancer
topic Tumor Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207476/
http://dx.doi.org/10.1210/jendso/bvaa046.1670
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