3. Understanding of molecular mechanism for cancer progression
1) Characterization of novel pathways of promoting colorectal cancer
♦ Colorectal cancer(CRC) is the third most common cancer and the second leading cause of cancer-related death world-wide. CRC exhibits molecular heterogeneity, which contributes to the variable clinical outcomes. Therefore, finding diverse potential therapeutic target is prior goal to defeat CRC.
To find out the effective targets with multi-function in cancer cell progression, we currently focus on Thrap3, a RNA binding protein and also transcription coactivator.
It has been reported that Thrap3 involves in pre-mRNA splicing and cyclin-D1 mRNA stability. Also Thrap3 can trigger nuclear mRNA decay which seems to be independent of nonsense-mediated decay involving premature stop codons (PTC) recognition.
Thrap3 Initially thought to be a transcriptional coactivator. Thrap3 enhances the transcriptional activation mediated by PPARG, through the stabilization of the PPARG binding to DNA in presence of ligand. Thrap3 also positively regulates the circadian clock by acting as a coactivator of the CLOCK-ARNTL/BMAL1 heterodimer and promotes its transcriptional activator activity and binding to circadian target genes.
Alterations in RNA metabolism and transcription of genes directly affect cell metabolism, proliferation, cell cycle, apoptosis or autophagy, immune responses or DNA damages which are indispensable modifications in cancer cells.
Therefore, we are studying the physiological roles of Thrap3 in CRC via its RNA metabolism modification.
♦ Throughout history, human-being has won the battle against deadly diseases, including cancers, by defeating them through prevention. Cancer growth inhibition is a global priority, but studying history suggests that the journey towards achieving this goal is difficult and full of detours and obstacles. To understand the molecular and cellular mechanisms of cancer progression through regulating autophagy and apoptosis, we currently focus on cancer-specific regulators which are critical for colorectal cancer progression.
· Flightless-1 (FLII), actin remodeling protein, which regulates its process. It has been reported that FLII regulates actin filaments by severing existed filaments and capping filament ends to make filament assembly into new cytoskeletal structures. Interestingly, there are some studies which demonstrate its novel roles in cancer progression, cancer cell migration, and metastasis. However, the exact molecular mechanisms how FLII regulates these phenomena are still unknown (Experimental & Molecular Medicine 2020). So, our lab currently focuses on the physiological roles of FLII in cancer growth via regulating autophagy and apoptosis.
2) Characterization of novel pathways of promoting leukemia
♦ CML: Type of cancer that affects the blood and bone marrow
Chronic myeloid leukemia (CML) is a myeloproliferative disorder. This cancer is characterized by presence of oncogenic fusion protein, tyrosine kinase, a BCR ABL. Several treatment for CML are developed , but the tyrosine kinase inhibitor(TKI) resistance is one of the limitation in CML therapy. So, it is necessary to find a target to inhibit the uncontrolled proliferation of immature blood cells and to alleviate TKI resistance effect.
♦ Thrap3 - a promising therapeutic target for leukemia.
Many studies showed that RNA Binding protein regulate leukemogenesis. Considering the role of Thrap3 in cellular physiology as mentioned above, it could regulate transcription, mRNA splicing of target gene related with regulation of proliferation, tyrosine kinase resistance. So, our research goal is to elucidate the function of Thrap3 in CML.
♦ Conflicts in transcription-replication lead to DNA damage and genomic instability, which are closely related to human diseases. A major source of these conflicts is the formation of R-loops that consist of an RNA-DNA hybrid and a displaced single-stranded DNA. Although these structures have been studied, many aspects of R-loop biology and R-loop-mediated genome instability remain unclear. Our lab demonstrate that Thrap3 plays a critical role in regulating R-loop resolution. Especially, in leukemic cancer cells, Thrap3 interacts with DEAD-Box Helicase 5 (DDX5) and localizes to R-loops. Arginine-mediated methylation of DDX5 is required for the interaction with Thrap3, and the Thrap3-DDX5 axis induces the recruitment of 5’-3’ exoribonuclease 2 (XRN2) into R-loops. The loss of Thrap3 increases R-loop accumulation and DNA damage (Experimental & Molecular Medicine 2021). These findings suggest that Thrap3 mediates resistance to cell death by preventing R-loop accumulation in cancer cells.