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MBTPS1 regulates proliferation of colorectal cancer primarily through its action on sterol regulatory element-binding proteins

Among the main metabolic pathways implicated in cancer cell proliferation are those of cholesterol and fatty acid synthesis, both of which are tightly regulated by sterol regulatory element-binding proteins (SREBPs). SREBPs are activated through specific cleavage by membrane-bound transcription fact...

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Autores principales: Hartal-Benishay, Liat H., Saadi, Esraa, Toubiana, Shir, Shaked, Lior, Lalzar, Maya, Abu Hatoum, Ossama, Tal, Sharon, Selig, Sara, Barki-Harrington, Liza
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9592115/
https://www.ncbi.nlm.nih.gov/pubmed/36300096
http://dx.doi.org/10.3389/fonc.2022.1004014
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author Hartal-Benishay, Liat H.
Saadi, Esraa
Toubiana, Shir
Shaked, Lior
Lalzar, Maya
Abu Hatoum, Ossama
Tal, Sharon
Selig, Sara
Barki-Harrington, Liza
author_facet Hartal-Benishay, Liat H.
Saadi, Esraa
Toubiana, Shir
Shaked, Lior
Lalzar, Maya
Abu Hatoum, Ossama
Tal, Sharon
Selig, Sara
Barki-Harrington, Liza
author_sort Hartal-Benishay, Liat H.
collection PubMed
description Among the main metabolic pathways implicated in cancer cell proliferation are those of cholesterol and fatty acid synthesis, both of which are tightly regulated by sterol regulatory element-binding proteins (SREBPs). SREBPs are activated through specific cleavage by membrane-bound transcription factor protease 1 (MBTPS1), a serine protease that cleaves additional substrates (ATF6, BDNF, CREBs and somatostatin), some of which are also implicated in cell proliferation. The goal of this study was to determine whether MBTPS1 may serve as a master regulator in proliferation of colorectal cancer (CRC). Tumors from CRC patients showed variable levels of MBTPS1 mRNA, which were in positive correlation with the levels of SREBPs and ATF6, and in reverse correlation with BDNF levels. Chemical inhibition of MBTPS1 activity in two CRC-derived cell lines resulted in a marked decrease in the levels of SREBPs, but not of its other substrates and a marked decrease in cell proliferation, which suggested that MBTPS1 activity is critical for proliferation of these cells. In accordance, CRISPR/Cas9 targeted knockout (KO) of the MBTPS1 gene resulted in the survival of only a single clone that presented a phenotype of severely attenuated proliferation and marked downregulation of several energy metabolism pathways. We further showed that survival of the MBTPS1 KO clone was dependent upon significant upregulation of the type-1 interferon pathway, the inhibition of which halted proliferation entirely. Finally, rescue of the MBTPS1 KO cells, resulted in partial restoration of MBTPS1 levels, which was in accordance with partial recovery in proliferation and in SREBP levels. These finding suggest that MBTPS1 plays a critical role in regulating colon cancer proliferation primarily through SREBP-associated lipid metabolism, and as such may serve as a possible therapeutic target in CRC.
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spelling pubmed-95921152022-10-25 MBTPS1 regulates proliferation of colorectal cancer primarily through its action on sterol regulatory element-binding proteins Hartal-Benishay, Liat H. Saadi, Esraa Toubiana, Shir Shaked, Lior Lalzar, Maya Abu Hatoum, Ossama Tal, Sharon Selig, Sara Barki-Harrington, Liza Front Oncol Oncology Among the main metabolic pathways implicated in cancer cell proliferation are those of cholesterol and fatty acid synthesis, both of which are tightly regulated by sterol regulatory element-binding proteins (SREBPs). SREBPs are activated through specific cleavage by membrane-bound transcription factor protease 1 (MBTPS1), a serine protease that cleaves additional substrates (ATF6, BDNF, CREBs and somatostatin), some of which are also implicated in cell proliferation. The goal of this study was to determine whether MBTPS1 may serve as a master regulator in proliferation of colorectal cancer (CRC). Tumors from CRC patients showed variable levels of MBTPS1 mRNA, which were in positive correlation with the levels of SREBPs and ATF6, and in reverse correlation with BDNF levels. Chemical inhibition of MBTPS1 activity in two CRC-derived cell lines resulted in a marked decrease in the levels of SREBPs, but not of its other substrates and a marked decrease in cell proliferation, which suggested that MBTPS1 activity is critical for proliferation of these cells. In accordance, CRISPR/Cas9 targeted knockout (KO) of the MBTPS1 gene resulted in the survival of only a single clone that presented a phenotype of severely attenuated proliferation and marked downregulation of several energy metabolism pathways. We further showed that survival of the MBTPS1 KO clone was dependent upon significant upregulation of the type-1 interferon pathway, the inhibition of which halted proliferation entirely. Finally, rescue of the MBTPS1 KO cells, resulted in partial restoration of MBTPS1 levels, which was in accordance with partial recovery in proliferation and in SREBP levels. These finding suggest that MBTPS1 plays a critical role in regulating colon cancer proliferation primarily through SREBP-associated lipid metabolism, and as such may serve as a possible therapeutic target in CRC. Frontiers Media S.A. 2022-10-10 /pmc/articles/PMC9592115/ /pubmed/36300096 http://dx.doi.org/10.3389/fonc.2022.1004014 Text en Copyright © 2022 Hartal-Benishay, Saadi, Toubiana, Shaked, Lalzar, Abu Hatoum, Tal, Selig and Barki-Harrington https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Hartal-Benishay, Liat H.
Saadi, Esraa
Toubiana, Shir
Shaked, Lior
Lalzar, Maya
Abu Hatoum, Ossama
Tal, Sharon
Selig, Sara
Barki-Harrington, Liza
MBTPS1 regulates proliferation of colorectal cancer primarily through its action on sterol regulatory element-binding proteins
title MBTPS1 regulates proliferation of colorectal cancer primarily through its action on sterol regulatory element-binding proteins
title_full MBTPS1 regulates proliferation of colorectal cancer primarily through its action on sterol regulatory element-binding proteins
title_fullStr MBTPS1 regulates proliferation of colorectal cancer primarily through its action on sterol regulatory element-binding proteins
title_full_unstemmed MBTPS1 regulates proliferation of colorectal cancer primarily through its action on sterol regulatory element-binding proteins
title_short MBTPS1 regulates proliferation of colorectal cancer primarily through its action on sterol regulatory element-binding proteins
title_sort mbtps1 regulates proliferation of colorectal cancer primarily through its action on sterol regulatory element-binding proteins
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9592115/
https://www.ncbi.nlm.nih.gov/pubmed/36300096
http://dx.doi.org/10.3389/fonc.2022.1004014
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