KDM4 Orchestrates Epigenomic Remodeling of Senescent Cells and Potentiates the Senescence-Associated Secretory Phenotype.

Boyi Zhang,Qilai Long,Xiaohui Ren,Jing Jiang,Hanxin Liu,Yu Sun,Xiaoling Zhang,James L Kirkland,Xing Chang,Judith Campisi,Qiang Fu,Eric W-F Lam,Liu Han,Min Qian,Shuling Song,Qixia Xu,Shanshan Wu,Jianming Guo

doi:10.1038/s43587-021-00063-1

Abstract

Cellular senescence restrains the expansion of neoplastic cells through several layers of regulation. We report that the histone H3-specific demethylase KDM4 is expressed as human stromal cells undergo senescence. In clinical oncology, upregulated KDM4 and diminished H3K9/H3K36 methylation correlate with poorer survival of prostate cancer patients post-chemotherapy. Global chromatin accessibility mapping via ATAC-seq, and expression profiling through RNA-seq, reveal global changes of chromatin openness and spatiotemporal reprogramming of the transcriptomic landscape, which underlie the senescence-associated secretory phenotype (SASP). Selective targeting of KDM4 dampens the SASP of senescent stromal cells, promotes cancer cell apoptosis in the treatment-damaged tumor microenvironment (TME), and prolongs survival of experimental animals. Our study supports dynamic changes of H3K9/H3K36 methylation during senescence, identifies an unusually permissive chromatin state, and unmasks KDM4 as a key SASP modulator. KDM4 targeting presents a novel therapeutic avenue to manipulate cellular senescence and limit its contribution to age-related pathologies including cancer.

Highlights

Senescence is a self-control mechanism that limits cell hyper-proliferation and prevents neoplastic progression by implementing a stable, durable, albeit generally irreversible growth arrest
To establish an unbiased epigenetic profile of senescent cells at the protein level, we chose to use stable isotope labeling with amino acids (SILACs), a mass spectrometry (MS)-based technique involving a non-radioactive isotope, to analyze senescent cells (SEN) induced by bleomycin (BLEO) and their proliferating counterparts (CTRL) (Fig. 1A)
When analyzing posttranslational modification (PTM) sites differentially modified between PRE and SEN cells, we noticed reduction of histone H3.2 signals in the categories of both dimethylated and trimethylated proteins, namely H3K27 and H3K36 (Fig. 1D) (Supplementary Table 3)

Summary

Introduction

Senescence is a self-control mechanism that limits cell hyper-proliferation and prevents neoplastic progression by implementing a stable, durable, albeit generally irreversible growth arrest. Senescent cells actively secrete a large array of proteins, many of which are pro-inflammatory factors per se, a property collectively termed the senescence-associated secretory phenotype (SASP) 2-4. Several lines of evidence suggest that the SASP is essential for tissue repair, wound healing, embryonic development, and immune surveillance to clear senescent cells 5. In a local tumor microenvironment (TME), the secretome of lingering senescent cells can markedly promote malignancy of neighboring cancer cells, chemoresistance, and cause chronic inflammation associated with many age-related disorders [7,8,9]. The harmful inflammation imposed by the SASP suggests that eliminating senescent cells or suppressing the SASP can be advantageous in multiple types of pathologies and not just cancer [8, 9, 11]

Methods

Results

Conclusion