Cargando…
Lineage-specific silencing of PSAT1 induces serine auxotrophy and sensitivity to dietary serine starvation in luminal breast tumors
A major challenge of targeting metabolism for cancer therapy is pathway redundancy, in which multiple sources of critical nutrients can limit the effectiveness of some metabolism-targeted therapies. Here, we analyze lineage-dependent gene expression in human breast tumors to identify differences in...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8845302/ https://www.ncbi.nlm.nih.gov/pubmed/35045283 http://dx.doi.org/10.1016/j.celrep.2021.110278 |
_version_ | 1784651645700800512 |
---|---|
author | Choi, Bo-Hyun Rawat, Vipin Högström, Jenny Burns, Philippa A. Conger, Kelly O. Ozgurses, Mete Emir Patel, Jaymin M. Mehta, Tejas S. Warren, Angelica Selfors, Laura M. Muranen, Taru Coloff, Jonathan L. |
author_facet | Choi, Bo-Hyun Rawat, Vipin Högström, Jenny Burns, Philippa A. Conger, Kelly O. Ozgurses, Mete Emir Patel, Jaymin M. Mehta, Tejas S. Warren, Angelica Selfors, Laura M. Muranen, Taru Coloff, Jonathan L. |
author_sort | Choi, Bo-Hyun |
collection | PubMed |
description | A major challenge of targeting metabolism for cancer therapy is pathway redundancy, in which multiple sources of critical nutrients can limit the effectiveness of some metabolism-targeted therapies. Here, we analyze lineage-dependent gene expression in human breast tumors to identify differences in metabolic gene expression that may limit pathway redundancy and create therapeutic vulnerabilities. We find that the serine synthesis pathway gene PSAT1 is the most depleted metabolic gene in luminal breast tumors relative to basal tumors. Low PSAT1 prevents de novo serine biosynthesis and sensitizes luminal breast cancer cells to serine and glycine starvation in vitro and in vivo. This PSAT1 expression disparity preexists in the putative cells of origin of basal and luminal tumors and is due to luminal-specific hypermethylation of the PSAT1 gene. Our data demonstrate that luminal breast tumors are auxotrophic for serine and may be uniquely sensitive to therapies targeting serine availability. |
format | Online Article Text |
id | pubmed-8845302 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
record_format | MEDLINE/PubMed |
spelling | pubmed-88453022022-02-15 Lineage-specific silencing of PSAT1 induces serine auxotrophy and sensitivity to dietary serine starvation in luminal breast tumors Choi, Bo-Hyun Rawat, Vipin Högström, Jenny Burns, Philippa A. Conger, Kelly O. Ozgurses, Mete Emir Patel, Jaymin M. Mehta, Tejas S. Warren, Angelica Selfors, Laura M. Muranen, Taru Coloff, Jonathan L. Cell Rep Article A major challenge of targeting metabolism for cancer therapy is pathway redundancy, in which multiple sources of critical nutrients can limit the effectiveness of some metabolism-targeted therapies. Here, we analyze lineage-dependent gene expression in human breast tumors to identify differences in metabolic gene expression that may limit pathway redundancy and create therapeutic vulnerabilities. We find that the serine synthesis pathway gene PSAT1 is the most depleted metabolic gene in luminal breast tumors relative to basal tumors. Low PSAT1 prevents de novo serine biosynthesis and sensitizes luminal breast cancer cells to serine and glycine starvation in vitro and in vivo. This PSAT1 expression disparity preexists in the putative cells of origin of basal and luminal tumors and is due to luminal-specific hypermethylation of the PSAT1 gene. Our data demonstrate that luminal breast tumors are auxotrophic for serine and may be uniquely sensitive to therapies targeting serine availability. 2022-01-18 /pmc/articles/PMC8845302/ /pubmed/35045283 http://dx.doi.org/10.1016/j.celrep.2021.110278 Text en https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ). |
spellingShingle | Article Choi, Bo-Hyun Rawat, Vipin Högström, Jenny Burns, Philippa A. Conger, Kelly O. Ozgurses, Mete Emir Patel, Jaymin M. Mehta, Tejas S. Warren, Angelica Selfors, Laura M. Muranen, Taru Coloff, Jonathan L. Lineage-specific silencing of PSAT1 induces serine auxotrophy and sensitivity to dietary serine starvation in luminal breast tumors |
title | Lineage-specific silencing of PSAT1 induces serine auxotrophy and sensitivity to dietary serine starvation in luminal breast tumors |
title_full | Lineage-specific silencing of PSAT1 induces serine auxotrophy and sensitivity to dietary serine starvation in luminal breast tumors |
title_fullStr | Lineage-specific silencing of PSAT1 induces serine auxotrophy and sensitivity to dietary serine starvation in luminal breast tumors |
title_full_unstemmed | Lineage-specific silencing of PSAT1 induces serine auxotrophy and sensitivity to dietary serine starvation in luminal breast tumors |
title_short | Lineage-specific silencing of PSAT1 induces serine auxotrophy and sensitivity to dietary serine starvation in luminal breast tumors |
title_sort | lineage-specific silencing of psat1 induces serine auxotrophy and sensitivity to dietary serine starvation in luminal breast tumors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8845302/ https://www.ncbi.nlm.nih.gov/pubmed/35045283 http://dx.doi.org/10.1016/j.celrep.2021.110278 |
work_keys_str_mv | AT choibohyun lineagespecificsilencingofpsat1inducesserineauxotrophyandsensitivitytodietaryserinestarvationinluminalbreasttumors AT rawatvipin lineagespecificsilencingofpsat1inducesserineauxotrophyandsensitivitytodietaryserinestarvationinluminalbreasttumors AT hogstromjenny lineagespecificsilencingofpsat1inducesserineauxotrophyandsensitivitytodietaryserinestarvationinluminalbreasttumors AT burnsphilippaa lineagespecificsilencingofpsat1inducesserineauxotrophyandsensitivitytodietaryserinestarvationinluminalbreasttumors AT congerkellyo lineagespecificsilencingofpsat1inducesserineauxotrophyandsensitivitytodietaryserinestarvationinluminalbreasttumors AT ozgursesmeteemir lineagespecificsilencingofpsat1inducesserineauxotrophyandsensitivitytodietaryserinestarvationinluminalbreasttumors AT pateljayminm lineagespecificsilencingofpsat1inducesserineauxotrophyandsensitivitytodietaryserinestarvationinluminalbreasttumors AT mehtatejass lineagespecificsilencingofpsat1inducesserineauxotrophyandsensitivitytodietaryserinestarvationinluminalbreasttumors AT warrenangelica lineagespecificsilencingofpsat1inducesserineauxotrophyandsensitivitytodietaryserinestarvationinluminalbreasttumors AT selforslauram lineagespecificsilencingofpsat1inducesserineauxotrophyandsensitivitytodietaryserinestarvationinluminalbreasttumors AT muranentaru lineagespecificsilencingofpsat1inducesserineauxotrophyandsensitivitytodietaryserinestarvationinluminalbreasttumors AT coloffjonathanl lineagespecificsilencingofpsat1inducesserineauxotrophyandsensitivitytodietaryserinestarvationinluminalbreasttumors |