Annual Report 2020

Laboratory of Fundamental Oncology

Rieko Ohki, Yu Chen, Ylenia Capodanno, Kiyono Aoki, Tatsuki Yamamoto, Yura Takahashi, Akane Sada, Yumi Shoji, Yukiko Sakaguchi, Estuko Oguro, Kota Uchiyama, Ayano Tajima, Kotoha Inoue

Introduction

 In the Laboratory of Fundamental Oncology, we are attempting 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 can lead to significant social contributions. Research on cancer-associated genes (tumor suppressor genes, oncogenes) has largely progressed with the advancement 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 explore 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 that 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 obvious that the loss of the transcriptional ability of p53 strongly promotes tumorigenesis. Several p53 target genes are directly related to cancer, such as the oncogene Mdm2 and the 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 conducted 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 have also demonstrated that PHLDA3 represses Akt activity in endocrine cells and that PHLDA3-deficient mice develop abnormalities in endocrine tissues. Collectively, these results indicated the existence of a novel p53-PHLDA3-mediated pathway of tumor suppression that is important for the development of NETs.

Education

 We have trained young researchers and students 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 appear 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, which imparts increasing importance to the modulation of p53 in both basic and applied research. We would also like to identify novel cancer-related genes, especially genes that are regulated by the tumor suppressor gene p53, and elucidate the mechanism of tumorigenesis. Through our research, we expect 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 2020

Journal

1 "Shiori Suzuki, Shuichi Tsutsumi, Yu Chen, Chikako Ozeki, Atsushi Okabe, Tatsuya Kawase, Hiroyuki Aburatani and Rieko Ohki*. Identification and characterization of the binding sequences and target genes of p53 lacking the 1st transactivation domain.  
Cancer Science, 111(2):451-466, 2020." 

2 Yu Chen and Rieko Ohki. p53-PHLDA3-Akt Network: The Key Regulators of Neuroendocrine Tumorigenesis. Int. J. Mol. Sci., 21(11), 4098, 2020.