Annual Report 2022
Division of Cancer Stem Cell
Kenkichi Masutomi, Mitsuhiro Machitani, Mami Yasukawa, Saori Ueki
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 for treating them. Specifically, our division studies the molecular links among 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) functions 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 TERT without affecting telomerase activity and that TERT 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 in vivo stem cell cycling even when telomere lengths are not limited. We found that RdRP activity directly contributes to cancer progression.
3. RdRP and anticancer drugs
We have confirmed a positive correlation between TERT protein expression levels and RdRP activity in various human cancer cell lines, indicating that RdRP inhibitors can be effective against various tumor types with high TERT expression levels. We continue to discover and characterize novel inhibitors of TERT-RdRP activity as potential 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 through our research activities.
List of papers published in 2022
Journal
1. Matsuda Y, Ye J, Yamakawa K, Mukai Y, Azuma K, Wu L, Masutomi K, Yamashita T, Daigo Y, Miyagi Y, Yokose T, Oshima T, Ito H, Morinaga S, Kishida T, Minamoto T, Kojima M, Kaneko S, Haba R, Kontani K, Kanaji N, Okano K, Muto-Ishizuka M, Yokohira M, Saoo K, Imaida K, Suizu F. Association of longer telomere length in cancer cells and cancer-associated fibroblasts with worse prognosis. Journal of the National Cancer Institute, 115:208-218, 2023
2. Niwa T, Tahara T, Chase CE, Fang FG, Nakaoka T, Irie S, Hayashinaka E, Wada Y, Mukai H, Masutomi K, Watanabe Y, Cui Y, Hosoya T . Synthesis of 11C-Radiolabeled Eribulin as a Companion Diagnostics PET Tracer for Brain Glioblastoma. Bull Chem Soc Jpn, 96:283-290, 2023
3. Matsuda Y, Yamashita T, Ye J, Yasukawa M, Yamakawa K, Mukai Y, Machitani M, Daigo Y, Miyagi Y, Yokose T, Oshima T, Ito H, Morinaga S, Kishida T, Minamoto T, Yamada S, Takei J, Kaneko MK, Kojima M, Kaneko S, Masaki T, Hirata M, Haba R, Kontani K, Kanaji N, Miyatake N, Okano K, Kato Y, Masutomi K. Phosphorylation of hTERT at threonine 249 is a novel tumor biomarker of aggressive cancer with poor prognosis in multiple organs. The Journal of pathology, 257:172-185, 2022
4. Machitani M, Takei J, Kaneko MK, Ueki S, Ohashi H, Watashi K, Kato Y, Masutomi K. Development of novel monoclonal antibodies against nsp12 of SARS-CoV-2. Virology journal, 19:213, 2022