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

Telma Costa ,Staffan Strömblad,Jonas Sjölund,Pablo Hernández-Varas,Peter D Adams,Uta Rabenhorst,Neil Robertson,Xiaoyi Gong ,Johan Hartman,Parisa Rabieifar,Emilia Turco,Míriam Masià-Balagué ,Miao Zhao,Kristian Pietras,Paola Defilippi,Ting Zhuang,Pernilla Roswall,Matthias Spiess,Julie Lorent,Helene Olofsson,Raoul V Kuiper ,Ran Ma

doi:10.1038/s41467-019-11510-4

Abstract

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.

Highlights

Overcoming cellular growth restriction, including the evasion of cellular senescence, is a hallmark of cancer
The PAK4 gene is located at a chromosomal region (19q13.2) frequently amplified in breast cancer with basal-like features[11] and consistently, PAK4 was found overexpressed in a small set of human breast cancer specimens[12]
PAK4 wt overexpression caused hyperplasia and, at a later stage, mammary tumors in a fraction of the mice comparable to the overexpression of catalytically active PAK140. This incomplete penetrance as well as the late tumor onset may suggest that to PAK1, PAK4 itself acts as a relatively weak oncogene and/or to facilitate tumor formation driven by other oncogene(s), the latter supported by the activating KRAS mutations that we observed in these tumors and the finding that PAK4 overexpression overcame RASinduced senescence in mammary epithelial cells

Summary

Introduction

Overcoming cellular growth restriction, including the evasion of cellular senescence, is a hallmark of cancer. 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-V12induced senescence. A PAK4 – RELB - C/EBPβ axis controls the senescencelike 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 oncogeneinduced senescence and reveal a selective vulnerability of cancer to PAK4 inhibition. While canonical NF-κB signaling (explicitly RELA) as well as CCAAT/enhancer-binding protein beta (C/EBPβ) are key transcriptional SASP regulators[8] and thereby firmly linked to cellular senescence, the potential involvement of noncanonical NF-κB signaling in senescence has remained largely unknown

Methods

Results

Conclusion