Annual Report 2020

Division of Cancer Stem Cell

Kenkichi Masutomi, Mitsuhiro Machitani, Mami Yasukawa, Saori Ueki, Daiki Yamamoto, Michie Yoshikawa

Introduction

 Research in the Division of Cancer Stem Cell is focused on deciphering the mechanisms that establish and maintain cancer stem cells and on developing novel therapeutic approaches to treat cancer stem cells. In particular, our division studies the molecular links between a) telomerase and RNA-dependent RNA polymerase (RdRP); b) TERT and cancer stem cells; and c) RdRP and anticancer drugs.

Research activities

1. Telomerase and RNA-dependent RNA polymerase

 Telomerase is a ribonucleoprotein complex that elongates telomeres. Human telomerase reverse transcriptase (TERT) is known as the catalytic subunit of telomerase and acts as an RNA-dependent DNA polymerase (RdDP), which synthesizes telomere DNA repeats from an RNA template TERC. Although the major function of TERT is believed to be telomere elongation, emerging evidence indicates that TERT exhibits various functions beyond telomere maintenance. We have reported that TERT has RNA-dependent RNA polymerase (RdRP) activity and synthesizes double-stranded RNA (dsRNA) in either a primer-dependent or primer-independent manner. Our recent studies have indicated that post-transcriptional phosphorylation of TERT enhances RdRP activity in hTERT without affecting telomerase activity and that hTERT RdRP negatively regulates the expression of tumor suppressor genes, eventually leading to cancer progression.

2. TERT and cancer stem cells

 Previous studies have indicated that TERT has activities beyond telomere maintenance, and it is speculated that the constitutive expression of TERT not only stabilizes telomere length and facilitates cell immortalization but also contributes to tumor susceptibility and alters stem cell cycling in vivo even when telomere lengths are not limited. We found that RdRP activity directly contributes to cancer progression

3. RdRP and anticancer drugs

 We further confirmed that TERT protein expression levels and RdRP activity are positively correlated in various human cancer cell lines, indicating that RdRP inhibitors can work effectively for many types of tumors with high TERT expression levels. We continue to discover and characterize novel inhibitors of TERT-RdRP activity as anticancer drugs.

Future Prospects

 We aim to contribute to the development of new therapeutic methods targeting cancer stem cells by advancing biochemical and molecular biological studies on the new functions of TERT, which were originally found by our research activities.

List of papers published in 2020

Journal

1. Machitani M, Yasukawa M, Nakashima J, Furuichi Y, Masutomi K. RNA-dependent RNA polymerase, RdRP, a promising therapeutic target for cancer and potentially COVID-19. Cancer Sci, 111:3976-3984, 2020