c-Myb and C/EBPβ regulate OPN and other senescence-associated secretory phenotype factors

Abstract

Tumorigenesis results from the convergence of cell autonomous mutations and corresponding stromal changes that promote tumor cell growth. Senescent cells, which secrete a plethora of pro-tumorigenic factors termed the senescence-associated secretory phenotype (SASP), play an important role in tumor formation. Investigation into SASP regulation revealed that many but not all SASP factors are subject to NF-kB and p38MAPK regulation. However, many pro-tumorigenic SASP factors, including osteopontin (OPN), are not responsive to these canonical pathways leaving the regulation of these factors an open question. We report that the transcription factor c-Myb regulates OPN, IL-6, and IL-8 in addition to 57 other SASP factors. The regulation of OPN is direct as c-Myb binds to the OPN promoter in response to senescence. Further, OPN is also regulated by the known SASP regulator C/EBPβ. In response to senescence, the full-length activating C/EBPβ isoform LAP2 increases binding to the OPN, IL-6, and IL-8 promoters. The importance of both c-Myb and C/EBPβ is underscored by our finding that the depletion of either factor reduces the ability of senescent fibroblasts to promote the growth of preneoplastic epithelial cells.

Liver osteopontin is required to prevent the progression of age‐related nonalcoholic fatty liver disease

“…Specifically, the accumulation of senescent hepatocytes has been shown to promote progression (Aravinthan & Alexander, 2016). Previous work has described osteopontin (OPN) as a senescence‐associated secretory phenotype (SASP) factor (Flanagan et al., 2017; Pazolli et al., 2009). Although senescence‐associated cell cycle exit likely evolved as an antitumor mechanism, SASP contains both anti‐ and pro‐tumorigenic potential (Lau & David, 2019).…”

“…Regarding its role as a metabolic modulator, it controls the fate of acetyl‐CoA in liver (Nunez‐Garcia et al., 2017; Nuñez‐Garcia et al., 2018) and rewires liver lipid metabolism after partial hepatectomy (Nuñez‐Garcia et al., 2018). OPN is considered a senescence‐associated secretory phenotype (SASP) factor (Flanagan et al., 2017; Pazolli et al., 2009). SASP factors are mainly cytokines, chemokines, and proteases with autocrine and paracrine effects that affect the neighboring cells and are able to induce senescence (Coppé, Desprez, Krtolica, & Campisi, 2010; Malaquin, Martinez, & Rodier, 2016).…”

Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance

“…Although former studies suggested the presence of C/EBP binding sites in the promoters of SASP factors, particularly a subset of CXCR2 ligands including IL-6, IL-8, GROα/β/γ (CXCL1/2/3), ENA-78 (CXCL5), and NAP2 (CXCL7) 46 , we extended the range of C/EBP-regulated SASP factors by adding SPINK1. Interestingly, a recent study reported that c-Myb and C/EBP co-regulate osteopontin (OPN) and many other SASP factors 50 , further suggesting the regulatory complexity.…”

Cellular Senescence in Kidney Fibrosis: Pathologic Significance and Therapeutic Strategies

“…In addition, SASP forms a stable positive loop via autocrine and paracrine mechanism, which leads to signal amplification (Herranz and Gil, 2018). The expression of the majority of SASP is regulated by nuclear factor κ-B (NF-κB), CCAT/enhancer binding protein-β (C/ EBP-β), p38 mitogen-activated protein kinase (MAPK) (Flanagan et al, 2018). DNA damage and oxidative stress activate NF-κB signaling, leading to overexpression of downstream SASP (Taniguchi and Karin, 2018;Wei and Ji, 2018).…”