Annual Report 2019
Laboratory of Fundamental Oncology
Rieko Ohki, Masahiro Takikawa, Kiyono Aoki, Ylenia Capodanno, Yu Chen, Masako Yamasaki, Akane Sada, Yumi Shoji, Usa Sano, Yukiko Sakaguchi, Kenta Amano, Mitsuhiro Tomosugi, Ayumi Suzuki, Estuko Oguro
Introduction
In the Laboratory of Fundamental Oncology, we are trying to elucidate the mechanism of tumorigenesis through the identification of novel cancer-related genes.
The most widespread cause of death among Japanese is “cancer”, and research aimed at overcoming cancer leads to great social contributions. Research on cancer-associated genes (tumor suppressor genes, oncogenes) has significantly progressed with the advance of molecular biology and cancer genomics, and many important genes have been identified. However, even for cancer types that are comparatively well-studied, such as lung cancer and breast cancer, there are only a few examples that can be explained by specific genetic abnormalities. Therefore, we still need to continue to search for novel cancer-associated genes.
The tumor suppressor gene p53 is the most frequently mutated gene in human cancers and plays a central role in the regulation of tumorigenesis. Elucidation of the tumor suppression ability of p53 and application of p53 research to cancer treatment and diagnosis is one of the most important goals to overcome cancer. p53 is a transcription factor which induces apoptosis, cell cycle arrest, DNA repair, etc., by transcriptionally activating p53 target genes. Mutations are detected within the DNA binding domain of p53 with a high frequency in cancer, and it is clear that the loss of the transcriptional ability of p53 strongly promotes tumorigenesis. Several p53 target genes are directly related to cancer, such as oncogene Mdm2 and tumor suppressor gene PTEN, and we aim to identify novel cancer-related genes by identifying novel p53 target genes.
The most important function of p53 is the transcriptional regulation of p53 target genes. We have performed an exhaustive screening of p53-inducible genes and reported the molecular function of several novel p53 target genes, including Noxa, Reprimo, AEN, FUCA1, IER5 and PHLDA3. These genes are involved in fundamental tumor suppression pathways, including apoptosis, growth suppression and stress response.
Research activities
PHLDA3 is a tumor suppressor gene encoding a repressor of Akt. PHLDA3 functions as a negative regulator of Akt (Cell, 136, 535-550, 2009) and a tumor suppressor gene that undergoes 2-hit inactivation in various neuroendocrine tumors (NETs) (PNAS, 111, E2404-E2413, 2014, and unpublished data). Furthermore, loss of PHLDA3 function in NETs is mutually exclusive with loss of p53 function, suggesting that PHLDA3 is a pivotal downstream mediator of p53 in NET suppression. We also demonstrated that PHLDA3 represses Akt activity in endocrine cells and that PHLDA3-deficient mice develop abnormalities in endocrine tissues. Collectively, these results indicate the existence of a novel p53-PHLDA3-mediated pathway of tumor suppression that is important for the development of NETs.
Education
Young researchers and students were trained in the laboratory of Fundamental Oncology.
Future prospects
The tumor suppressor gene, p53, is recognized by researchers in the field as one of the most important genes in cancer research. While it may seem that p53 has already been well-studied by many researchers, and that many of its functions have already been elucidated, we are pursuing our research with the conviction that there remain many functions yet to be discovered. We also believe that p53 will be an important target in future applications such as cancer treatment and diagnosis. In contrast to receptors and transporters located on the cell surface, p53 is a transcription factor located in the nucleus and has thus been regarded as a difficult drug target. However, inhibitors of nuclear factors have been more successfully developed in recent years, and this makes modulation of p53 of increasing importance in both basic and applied research. We would also like to identify novel cancer-related genes, especially genes that are regulated by tumor suppressor gene p53, and elucidate the mechanism of tumorigenesis. Through our research, we hope that we can contribute to the development of novel diagnosis and treatment methods, and respond to the unmet medical needs of cancer patients.
List of papers published in 2019
Journal
1. Suzuki S, Tsutsumi S, Chen Y, Ozeki C, Okabe A, Kawase T, Aburatani H, Ohki R. Identification and characterization of the binding sequences and target genes of p53 lacking the 1st transactivation domain. Cancer Sci, 111:451-466, 2020
2. Yamano S, Kimura M, Chen Y, Imamoto N, Ohki R. Nuclear import of IER5 is mediated by a classical bipartite nuclear localization signal and is required for HSF1 full activation. Exp Cell Res, 386:111686, 2020
3. Su A, Wang S, Sada A, Otani Y, Zhai L, Liu X, Sayama M, Ohki R, Ohwada T. Non-naturally Occurring Helical Molecules Can Interfere with p53-MDM2 and p53-MDMX Protein-Protein Interactions. Chem Pharm Bull (Tokyo), 67:1139-1143, 2019
4. Wang S, Otani Y, Zhai L, Su A, Nara M, Kawahata M, Yamaguchi K, Sada A, Ohki R, Ohwada T. Overall Shape Constraint of Alternating α/β-Hybrid Peptides Containing Bicyclic β-Proline. Org Lett, 21:7813-7817, 2019
5. Tatsuya Kawase, Yu Chen, Rieko Ohki. IER5 Is a p53-Regulated Activator of HSF1 That Contributes to Promotion of Cancer. Heat Shock Proteins in Signaling Pathways, Chapter 13, Heat Shock Proteins, Vol. 17, pp. 253-272, 2019