Shayan Ahmed, Jamia Millia Islamia, New Delhi
Cancer stem cells (CSCs) have recently been discovered in a number of different cancers, including pancreatic cancers. These are called pancreatic cancer stem cells (PCSCs). Pancreatic cancer is a frequently occurring cancer with a bad prognosis. Evidence suggests that sirtuin 1 (SIRT1) has biological activities that contribute to pancreatic cancer development and spread. SIRT1 collaborates as a functional unit with the Cullin 4B (CUL4B)-Ring E3 ligase (CRL4B) complex and promotes cancer development. SIRT1 and CUL4B, therefore, are potential oncogenes and biomarkers that might be used as tumor therapeutic targets.
SIRT1 & CRL4B Complex
SIRT1 plays a key role in cancer development by inhibiting apoptosis and stimulating cell proliferation and angiogenesis. SIRT1 levels over a certain threshold are linked to poorly differentiated pancreatic ductal carcinomas. Also, SIRT1 aids pancreatic cancer chemoresistance by regulating chemotherapeutic-induced adaptive responses in cells under stress. The CRL4B complex controls transcription repression by promoting monoubiquitination of histone H2AK119. CRL4B also physically interacts with polycomb repressive complex 2 (PRC2) or the SUV39H1/HP1/DNMT3A complex. This interaction furthers inhibits the transcription of many tumor suppressors and encourages tumorigenesis. SIRT1 and CUL4B have been shown to mutually stimulate PCSCs proliferation, autophagy, and invasion. SIRT1 is crucial for pancreatic cancer tumorigenesis and stemness stability, implying that SIRT1 should be pursued as a cancer treatment target.
Role of SIRT1/CRL4B Complex Interaction in Development of Pancreatic Cancer
SIRT1 participates in the proliferation, autophagy, invasion, and stemness of pancreatic cancer, in collaboration with the CRL4B complex.
Figure 1. A schematic representation depicting the mechanism of SIRT1/CRL4B complex in controlling proliferation, autophagy, invasion, and stemness of pancreatic carcinogenesis.
- Role in Cell Proliferation: SIRT1 deacetylates pancreatic transcription factor-1a and β-catenin, which governs acinar-to-ductal metaplasia. In pancreatic cancer, E-cadherin transcription suppression is associated with SIRT1; SIRT1 has the ability to silence the E-cadherin promoter. This elucidates SIRT1’s oncogenic mechanism. GRHL3 has been identified as the target gene of the SIRT1/CRL4B complex. GRHL3 expression was substantially decreased in tumor tissues that overexpressed SIRT1. SIRT1/CRL4B complex transcriptionally reduced GRHL3 expression, limiting cell differentiation and providing an essential mechanistic foundation for SIRT1 function in PCSCs. Another target gene FOXO3 was also identified, functionally involved in cell differentiation, growth, and migration.
- Role in Autophagy: PCSCs can be suppressed by inhibiting autophagy, SIRT1 promotes autophagy. SIRT1 has the ability to directly deacetylate LC3, Atg5, Atg7, and Atg8, which are essential components of the autophagy process. The SIRT1/CRL4B complex operates as a whole, and co-phenotypic studies with SIRT1 revealed that CUL4B was positively associated with autophagy in pancreatic cancer.
- Role in Invasion: SIRT1 can increase mesenchymal marker expression, decrease epithelial marker expression, and accelerate pancreatic cancer cell invasion. This emphasizes that SIRT1 has a positive role in promoting epithelial-mesenchymal transition (EMT).
- Role in Stemness: Besides promoting tumor development, SIRT1 also promotes tumor-initiating capability and CSC frequency, elucidating its function in PCSCs promotion. Further research into the precise mechanism that causes stemness is needed.
- Other Roles: The SIRT1/CRL4B complex triggers H2AK119 monoubiquitination (H2AK119ub1). The SIRT1/CRL4B complex formed on target promoters, resulting in a deacetylated H3K9, H3K14, and H4K16/H2AK119ub1 corepressed ‘histone code,’ thereby limiting transcription of target genes, GRHL3 and FOXO3.
Also read: Differentiation pathways in human Treg cells revealed
Source:
Leng, S., Huang, W., Chen, Y., Yang, Y., Feng, D., Liu, W., Gao, T., Ren, Y., Huo, M., Zhang, J., Yang, Y., & Wang, Y. (2021). SIRT1 coordinates with the CRL4B complex to regulate pancreatic cancer stem cells to promote tumorigenesis. Cell death and differentiation, 10.1038/s41418-021-00821-z. Advance online publication. https://doi.org/10.1038/s41418-021-00821-z
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About the Author: Shayan Ahmed is currently pursuing a Master of Science degree in Microbiology from the Department of Biosciences, Jamia Millia Islamia, New Delhi. His area of research interest lies in antibiotic resistance and associated molecular mechanisms. His recent work was focused on understanding colistin resistance patterns in the environment, particularly in water bodies.
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