Handling Editor: David Stephens
ABSTRACT
Molecular details of how endocytosis contributes to oncogenesis remain elusive. Our in silico analysis of colorectal cancer (CRC) patients revealed stage-dependent alterations in the expression of 112 endocytosis-related genes. Among them, transcription of the endosomal sorting complex required for transport (ESCRT)-I component VPS37B was decreased in the advanced stages of CRC. Expression of other ESCRT-I core subunits remained unchanged in the investigated dataset. We analyzed an independent cohort of CRC patients, which also showed reduced VPS37A mRNA and protein abundance. Transcriptomic profiling of CRC cells revealed non-redundant functions of Vps37 proteins. Knockdown of VPS37A and VPS37B triggered p21 (CDKN1A)-mediated inhibition of cell proliferation and sterile inflammatory response driven by the nuclear factor (NF)-κB transcription factor and associated with mitogen-activated protein kinase signaling. Co-silencing of VPS37C further potentiated activation of these independently induced processes. The type and magnitude of transcriptional alterations correlated with the differential ESCRT-I stability upon individual and concurrent Vps37 depletion. Our study provides novel insights into cancer cell biology by describing cellular stress responses that are associated with ESCRT-I destabilization.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: K.K., E.S., M. Mikula, M. Miączyńska; Methodology: K.K., P.E., E.S., A.S.-C., E.D.-W., M.B.-O., M. Mikula; Formal analysis: K.K., P.E., B.S., E.S., K.G., A.S.-C., E.D.-W., M.B.-O., K.P., M.P.-S., M. Mikula, M. Miączyńska; Investigation: K.K., P.E., E.S., B.S., E.D.-W., M.B.-O.; Resources: M. Miączyńska; Data curation: K.K., K.G., K.P., M.P.-S., M. Mikula, M. Miączyńska; Writing - original draft: K.K., M. Miączyńska; Writing - review & editing: K.K., P.E., B.S., E.S., A.S.-C., M.B.-O., K.P., M.P.-S., M. Mikula, M. Miączyńska; Supervision: K.K., M. Miączyńska; Funding acquisition: M. Miączyńska.
Funding
This study was financed by a TEAM grant (POIR.04.04.00-00-20CE/16-00), and K.P. was supported by a TEAM-TECH Core Facility Plus/2017–2/2 grant (POIR.04.04.00-00-23C2/17-00) – both grants are from the Fundacja na rzecz Nauki Polskiej co-financed by the European Union under the European Regional Development Fund. E.S. was supported by a Sonata grant (2016/21/D/NZ3/00637) from the Narodowe Centrum Nauki.
Data availability
RNA-Seq datasets reported in this paper have been deposited to GEO under the accession number GSE152195.
Supplementary information
Supplementary information available online at https://jcs.biologists.org/lookup/doi/10.1242/jcs.250951.supplemental
- Received July 7, 2020.
- Accepted November 9, 2020.
- © 2021. Published by The Company of Biologists Ltd
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