Research Projects

Cellular senescence is the state of irreversible cell cycle arrest that can be induced by a variety of potentially oncogenic stimuli and has therefore long been considered to suppress tumorigenesis, acting as a guardian of homeostasis. Emerging evidence, however, reveals that senescent cells also promote secretion of various inflammatory and pro-proliferative factors. This newly identified senescence-associated phenotype termed SASP is likely to be associated with homeostatic disorders including cancer. It is therefore quite possible that accumulation of senescent cells during aging or obesity in vivo may contribute to aging- and/or obesity-associated cancers. By conducting the following studies, we aim to clarify the molecular mechanisms underlying aging- and/or obesity-associated cancer.

1. Regulation of tumorigenesis by cellular senescence.

During the past few decades, we have revealed that p16INK4a cyclin-dependent kinase inhibitor has a key role in establishing stable G1 cell-cycle arrest through activating the retinoblastoma (Rb) tumor suppressor protein in senescent cells (Hara et al., Mol. Cell. Biol. 1996; Ohtani et al., Nature 2001).・However, since the p16INK4a/Rb-pathway also induces elevated levels of reactive oxygen species (ROS) (Takahashi et al., Nat. Cell Biol. 2006; Imai et al., Cell Rep. 2014) and excess ROS is a well known DNA damaging agent, it is possible that although the onset of cellular senescence initially acts as a barrier to cancer, it may eventually promote tumorigenesis, contributing to aging- and/or obesity-associated increase in cancer.・We are currently focusing on this point in aiming to understand the relationship between cellular senescence and cancer.


2. The roles and mechanisms of SASP.

In addition to stable cell cycle arrest, senescent cells also develop SASP, which contributes positively and negatively to cancer development, depending on the biological context.・Despite considerable progress in understanding biological roles of SASP, far less is known about how the SASP is induced.・We have recently found that, in senescent cells, the DNA damage response (DDR) induces SASP through proteasomal degradation of G9a and GLP, major histone 3 lysine 9 (H3K9) mono- and dimethyltransferases (Takahashi et al., Mol. Cell 2012).・、 greater understanding of the molecular mechanisms involved will lead to novel therapeutic strategies for aging- and/or obesity-associated cancer.

3. Understanding the roles of cellular senescence in vivo.

Optical imaging by bioluminescence allows a non-invasive and real-time analysis of various biological responses, such as gene expression, in living animals.・Recently, we have generated transgenic mice lines expressing the firefly luciferase under the control of the p16INK4a or p21Waf1/Cip1 senescence gene promoters(Ohtani et al., PNAS 2007; Yamakoshi et al., J. Cell Biol. 2009).・Using these senescence response imaging mice, we are currently investigating the timing and hence, likely roles and mechanisms of cellular senescence in vivo.

4. The roles and mechanisms of gut microbiota in obesity-associated cancer.

Although several phenomena have been proposed to explain how obesity increases cancer risk, the exact molecular mechanisms that integrate these phenomena have remained largely obscure.・ Recently, we have traced the association between obesity and increased cancer risk to gut microbiota communities that produce a DNA-damaging bile acid.・The analyses also revealed that DNA-damaging bile acid promotes obesity-associated liver cancer development by inducing SASP in hepatic stellate cells (Yoshimoto et al., Nature 2013).・We are now embarking on the next steps, focusing on the potential clinical implications of these findings.


Recent key publications(*Corresponding author)

  1. Sato S, Kawamata Y, Takahashi A, Imai Y, Hanyu A, Okuma A, Takasugi M, Yamakoshi K, Sorimachi H, Kanda H, Ishikawa Y, Sone S, Nishioka Y,*Ohtani N, & *Hara E.
    Ablation of the p16INK4a tumour suppressor reverses ageing phenotypes of klotho mice.
    Nature Communications 2015 Apr 29;6:7035.
  2. Imai Y, Takahashi A, Hanyu A, Hori S, Sato S, Naka K, Hirao A, Ohtani N, &*Hara E.
    Crosstalk between the Rb pathway and AKT signaling forms a quiescence-senescence switch.
    Cell Reports 2014 Apr 10;7(1):194-207.
  3. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, Iwakura Y, Oshima K, Morita H, Hattori M, Honda K, Ishikawa Y, *Hara E, & Ohtani N.
    Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome.
    Nature. 2013 Jul 4;499(7456):97-101.
  4. Takahashi A, Imai Y, Yamakoshi K, Kuninaka S, Ohtani N, Yoshimoto S, Hori S, Tachibana M, Anderton E, Takeuchi T, Shinkai Y, Peters G, Saya H, &*Hara E.
    DNA damage signaling triggers degradation of histone methyltransferases through APC/CCdh1 in senescent cells.
    Molecular Cell 2012 Jan 13;45(1):123-31.
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