PAK4 suppresses RELB to prevent senescence-like growth arrest in breast cancer

Published on Dec 1, 2019in Nature Communications11.878
· DOI :10.1038/s41467-019-11510-4
Tânia D. F. Costa2
Estimated H-index: 2
(KI: Karolinska Institutet),
Ting Zhuang4
Estimated H-index: 4
(KI: Karolinska Institutet)
+ 19 AuthorsStaffan Strömblad30
Estimated H-index: 30
(KI: Karolinska Institutet)
Overcoming cellular growth restriction, including the evasion of cellular senescence, is a hallmark of cancer. We report that PAK4 is overexpressed in all human breast cancer subtypes and associated with poor patient outcome. In mice, MMTV-PAK4 overexpression promotes spontaneous mammary cancer, while PAK4 gene depletion delays MMTV-PyMT driven tumors. Importantly, PAK4 prevents senescence-like growth arrest in breast cancer cells in vitro, in vivo and ex vivo, but is not needed in non-immortalized cells, while PAK4 overexpression in untransformed human mammary epithelial cells abrogates H-RAS-V12-induced senescence. Mechanistically, a PAK4 - RELB - C/EBPβ axis controls the senescence-like growth arrest and a PAK4 phosphorylation residue (RELB-Ser151) is critical for RELB-DNA interaction, transcriptional activity and expression of the senescence regulator C/EBPβ. These findings establish PAK4 as a promoter of breast cancer that can overcome oncogene-induced senescence and reveal a selective vulnerability of cancer to PAK4 inhibition.
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