Degradome-focused RNA interference screens to identify proteases important for breast cancer cell growth.
RNA interference
breast cancer
degradome
genetic screen
protease
Journal
Frontiers in oncology
ISSN: 2234-943X
Titre abrégé: Front Oncol
Pays: Switzerland
ID NLM: 101568867
Informations de publication
Date de publication:
2022
2022
Historique:
received:
02
06
2022
accepted:
20
09
2022
entrez:
31
10
2022
pubmed:
1
11
2022
medline:
1
11
2022
Statut:
epublish
Résumé
Proteases are known to promote or impair breast cancer progression and metastasis. However, while a small number of the 588 human and 672 murine protease genes have been extensively studied, others were neglected. For an unbiased functional analysis of all genome-encoded proteases, i.e., the degradome, in breast cancer cell growth, we applied an inducible RNA interference library for protease-focused genetic screens. Importantly, these functional screens were performed in two phenotypically different murine breast cancer cell lines, including one stem cell-like cell line that showed phenotypic plasticity under changed nutrient and oxygen availability. Our unbiased genetic screens identified 252 protease genes involved in breast cancer cell growth that were further restricted to 100 hits by a selection process. Many of those hits were supported by literature, but some proteases were novel in their functional link to breast cancer. Interestingly, we discovered that the environmental conditions influence the degree of breast cancer cell dependency on certain proteases. For example, breast cancer stem cell-like cells were less susceptible to depletion of several mitochondrial proteases in hypoxic conditions. From the 100 hits, nine proteases were functionally validated in murine breast cancer cell lines using individual knockdown constructs, highlighting the high reliability of our screens. Specifically, we focused on mitochondrial processing peptidase (MPP) subunits alpha (Pmpca) and beta (Pmpcb) and discovered that MPP depletion led to a disadvantage in cell growth, which was linked to mitochondrial dysfunction.
Identifiants
pubmed: 36313646
doi: 10.3389/fonc.2022.960109
pmc: PMC9598039
doi:
Types de publication
Journal Article
Langues
eng
Pagination
960109Informations de copyright
Copyright © 2022 Hölzen, Syré, Mitschke, Brummer, Miething and Reinheckel.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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