メニュー

Outline - Department of Biochemistry Kindai University Faculty of Medicine

  • JAPANESE
  • ENGLISH

Research

Outline of our study

promo.png

Our aims

One out of two people will develop cancers and one in three people will die of these malignant diseases in Japan. Because of the expansion of the aging population, cancer incidence and mortality are expected to increase in future. Thus, it will become much more important for us to further understand cancer biology and apply our knowledge to improve the efficacies of treatment and early diagnosis. In spite of recent medical advances and subsequent significant improvements in cancer treatment, substantial unsolved problems still exist, which include cancers with difficulty in early diagnosis, therapeutic resistance, recurrence, and metastasis.

Dynamic interactions between environmental factors and genetic diversities/abnormalities are thought to drive tumorigenesis. A recent advance in technology including the next generation sequencing technology has enormously enhanced our knowledge in cancer biology. However, many questions still linger such as how normal cells, precancerous and cancer cells react to the extrinsic and intrinsic selection pressures in the course of malignant transformation, how cell fate is determined, and how the selection processes are regulated. Recent findings suggest that cancer cells are able to adapt to their surrounding environment and escape from cancer surveillance mechanisms by epigenetic reprograming at the very early stage of malignant transformation, hence enabling their survival and continuous proliferation. We will address these pathophysiological issues from the perspectives of environmental response and epigenetic regulation in order to identify novel therapeutic targets and diagnostic markers for cancer treatment and prevention.

Epigenetics is defined as “stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence”, encompassing the modifications of DNA binding proteins (e.g. histones), DNA, RNA, and noncoding RNAs. Recent accumulating lines of evidence have indicated that epigenetics strongly contributes to the acquisition of biological properties of cancer cells from their very early to later stages of proliferation. Thus, in order to develop an innovative strategy for cancer prevention and treatment, we need deeper understandings on the regulatory mechanisms of the responses to intrinsic and extrinsic cellular changes in vivo. We mainly employ genetically modified mouse models and cultured cells to analyze their phenotypic alterations using epigenomic, cell biological, biochemical approaches and imaging technologies. We are also expanding our research field to ageing biology for searching potential routes to cancer prevention.

Outlines of our past research

1. Apoptosis regulation

We have studied apoptosis as a phenotype of environmental responses. Deregulated apoptosis is a hallmark of cancer. In fact, deregulation of apoptosis regulators is closely associated with multiple processes of tumorigenesis. We are focusing on the genes involved in nuclear signaling and apoptosis regulation, and examine the underlying molecular mechanisms with special emphasis on the TP53 signaling pathway.

Okada H, Suh WK, Jin J, Woo M, Du C, Elia A, Duncan GS, Wakeham A, Itie A, Lowe SW, Wang X, Mak TW. Generation and characterization of Smac/Diablo-deficient mice. Mol Cell Biol. 22:3509-3517 (2002)

Okada H*, Bakal C, Shahinian A, Elia A, Wakeham A, Suh WK, Duncan GS, Ciofani M, Rottapel R, Zuniga-Pflucker JC, Mak TW. Survivin loss in thymocytes triggers p53-mediated growth arrest and p53-independent cell death. J Exp Med. 199:399-410 (2004) (*Corresponding author)

Sasaki T, Marcon E, McQuire T, Arai Y, Moens PB, Okada H. Bat3 deficiency accelerates the degradation of Hsp70-2/Hspa2 during spermatogenesis. J Cell Biol. 182:449-458 (2008)

image_03.png

J Exp Med. Vol. 199, 3. Cover art by Graham Hutcheson

2. DNA damage response

image_04.png

As a response to extrinsic environmental signals, we focus on DNA damage response. Deregulation of DNA damage response and repair mechanisms lead to genomic instability, malignant transformation and heterogeneity of cancer, thus contributing to malignancy grade and aggravating therapeutic response. DNA damage response also has associated with regulation of epigenetics. We are focusing on the regulatory mechanisms of DNA double-strand break repair.

Sasaki T, Gan EC, Wakeham A, Kornbluth S, Mak TW, Okada H. HLA-B-associated transcript 3 (Bat3)/Scythe is essential for p300-mediated acetylation of p53. Genes Dev. 21:848-861 (2007)

Tong KI, Ota K, Komuro A, Ueda T, Ito A, Koch AC, Okada H. Attenuated DNA damage repair delays therapy-related myeloid neoplasms in a mouse model Cell death & Disease (in press)

3. Histone methylation

image_02.png

In addition to genetic alterations, long- and short-term gene expression patterns established by epigenetics in response to environmental signals make a significant contribution to malignant transformation. However, the details of the epigenetics-mediated regulation of tumorigenesis are still unclear, especially in vivo. We are studying their roles in cancer development by focusing on the regulatory mechanisms of histone methylation and chromatin remodeling.

Kawazu M, Saso K, Tong KI, McQuire T, Goto K, Son D-O, Wakeham A, Miyagishi M, Mak TW, Okada H. Histone demethylase Jmjd2b functions as a co-factor of estrogen receptor in breast cancer proliferation and mammary gland development.
PLoS One. 6:e17830 (2011)