Department of Biochemistry and Molecular Biology

Chang Gung University Academic Capacity Ensemble

Research directions and laboratory features

Our laboratory focuses on elucidating the roles and regulatory mechanisms of cytidine triphosphate synthase (CTPS) filament formation in cancer development and Drosophila melanogaster development.

CTP synthase (CTPS) is an essential metabolic enzyme required for cell growth, catalyzing the synthesis of cytidine triphosphate (CTP). CTP is a fundamental building block for DNA and RNA synthesis and also plays critical roles in lipid biosynthesis and glycosylation. To sustain rapid proliferation, cancer cells reprogram their metabolic pathways and become highly dependent on nutrients such as glucose and glutamine. However, nutrient depletion—particularly glutamine limitation—is a common stress within the tumor microenvironment.

Our research demonstrates that under such nutrient stress conditions, cancer cells adapt by forming CTPS filaments, which modulate metabolic activity and promote cell survival. We further show that CTPS filaments associate with the cytoskeleton, and that filament formation enhances tumor growth, highlighting the importance of metabolic enzyme spatial organization in cancer progression.

In addition to cancer biology, we investigate the physiological roles of CTPS filament formation in vivo using Drosophila. We observe highly conserved CTPS filaments in germline cells (egg chambers) and demonstrate that CTPS assembly regulates enzymatic activity to meet the high demand for rapid DNA replication. These findings underscore the significance of spatially organized biochemical reactions in cellular physiology and developmental processes.

By integrating genetics, proteomics, metabolomics, and genomics, our laboratory systematically dissects the adaptive mechanisms employed by cancer cells under nutrient stress. We also investigate how post-translational modifications, such as ubiquitination and methylation, regulate CTPS filament assembly, providing mechanistic insights into their roles in cancer and development.

Our laboratory integrates genomics, metabolomics, and proteomics to systematically dissect the adaptive mechanisms employed by cancer cells under nutrient stress. We focus on understanding how cancer cells dynamically regulate CTPS filament formation to maintain metabolic homeostasis and promote survival. In parallel, we aim to explore whether this stress-adaptive strategy can be pharmacologically targeted, thereby opening new avenues for cancer therapy.

Our major research interests include:

1.       Elucidating the mechanisms of CTPS filament formation in Drosophila germ cells (egg chambers and sperm), and determining their roles in cell cycle regulation and cellular differentiation.

2.       Defining the molecular mechanisms by which cancer cells regulate CTPS filament dynamics under glutamine-deprived conditions, and assessing their impact on cell survival and tumor growth.

3.       Evaluating the therapeutic potential of targeting CTPS filament assembly and stability, with the goal of developing novel metabolism-based anticancer strategies.

Through these studies, we aim to define the functional and regulatory roles of CTPS filament formation in cellular physiology and tumorigenesis, and to provide a conceptual framework for the development of next-generation anticancer therapies.

Publication

1.      Wei-Cheng Lin, Chun-Yen Wang, Kuang-Jing Huang, Archan Chakraborty, Yu-Tsun Lin, Ya-Ju Hsieh, Kun-Yi Chien, Po-Yuan Ke, Wei-Han Huang, Chih-Yun Cheng, Ian Yi-Feng Chang, Hsiang-Yu Tang, Cheng-Hung Yang, Mei-Ling Cheng, Ying-Chih Chang, Chau-Ting Yeh, Chien-Kuo Lee, Jau-Song Yu, Yu-Sun Chang, Jörg Großhans, and Li-Mei Pai*. (2026) HSPB8 regulates CTP synthase filaments to couple nucleotide metabolism and autophagy in tumors. Under submission.

2.      Pei-Yu Wang, Archan Chakraborty, Hsin-Ju Ma, Jhen-Wei Wu, Anna C-C Jang, Wei-Cheng Lin, Hai-Wei Pi, Chau-Ting Yeh, Mei-Ling Cheng, Jau-Song Yu, Li-Mei Pai^*. (2022) Drosophila CTP synthase regulates collective cell migration by controlling the polarized endocytic cycle. Development, 149(16). doi:10.1242/dev.200190 (SCI).

3.      Archan Chakraborty, Wei-Cheng Lin, Yu-Tsun Lin, Kuang-Jing Huang, Pei-Yu Wang, Yi-Feng Chang, Hsiang-Iu Wang, Kung-Ting Ma, Chun-Yen Wang, Xuan-Rong Huang, Yen-Hsien Lee, Bi-Chang Chen, Ya-Ju Hsieh, Kun-Yi Chien, Tzu-Yang Lin, Ji-Long Liu, Li-Ying Sung, Jau-Song Yu, Yu-Sun Chang and Li-Mei Pai^*. (2020) SNAP29 mediates the assembly of histidine-induced CTPS filaments along cytokeratin network. Journal of Cell Science 139(9):ics240200. Doi:10.1242/jcs.240200. SCI.

4.      Wei-Cheng Lin, Archan Chakraborty, Shih-Chia Huang, Pei-Yu Wang, Ya-Ju, Hsieh, Kun-Yi Chien, Yen-Hsien Lee, Chia-Chun Chang, Hsiang-Yu Tang, Yu-Tsun Lin, Chang-Shung Tung, Ji-Dung Luo, Ting-Wen Chen, Tzu-Yang Lin, Mei-Ling Cheng, Yi-Ting Chen, Chau-Ting Yeh; Ji-Long Liu, Li-Ying Sung, Ming-Shi Shiao, Jau-Song Yu, Yu-Sun Chang, Li-Mei Pai*. (2018) Histidine-dependent protein methylation is required for the compartmentalization of CTPS. Cell Reports doi.org/10.1016/j.celrep.2018.24(10)2733-2745. SCI.
5. Pei-Yu Wang, Wei-Cheng Lin, Yi-Cheng Tsai, Mei-Ling Cheng, Yu-Hung Lin, Shu-Heng Tseng, Archan Chakraborty, Li-Mei Pai*. (2015. 11) Regulation of CTP Synthase Filament Formation During DNA Endoreplication in Drosophila. Genetics. 201: 1511-1523. SCI.