November 3rd, 2024
Recent Publications Harnessing the Power of Translatomics
Every week we provide a digest of a small number of recent interesting papers in the field of translatomics.
In this week’s Sunday papers, several groups of researchers used polysome profiling techniques to study gastric cancer at the molecular level. Chang et al. showed that PUS7-mediated pseudouridylation boosted ALKBH3 mRNA translation that is associated with gastric cancer cell proliferation. Yu et al. discovered that Helicobacter pylori drove the formation of hnRNPA2B1-PABPC1 complex to elevate the tumour-related genes. Park et al. identified that SMYD5 methylates ribosomal protein L40 to improve ribosome biogenesis and function of cancer-associated proteins.
PUS7-dependent pseudouridylation of ALKBH3 mRNA inhibits gastric cancer progression
Clinical and translational medicine, 2024
Chang, Y., Jin, H., Cui, Y., Yang, F., Chen, K., Kuang, W., Huo, C., Xu, Z., Li, Y., Lin, A. and Yang, B.
Gastric cancer is characterized by its ability to rapidly grow and metastasize, contributing to poor patient outcomes and high mortality rates. The enzyme PUS7 is known for its role in pseudouridylation, which is a chemical modification of RNA, for influencing RNA stability and function. The authors investigated how PUS7 affected the mRNA of ALKBH3, a gene with potential tumour-suppressing properties, in the context of gastric cancer.
PUS7 was shown to modify ALKBH3 mRNA by adding pseudouridine, a modified RNA nucleotide. It stabilized the ALKBH3 mRNA and enhanced its translation into protein. Polysome profiling revealed that PUS7-mediated pseudouridylation influenced ALKBH3 mRNA translation efficiency by increasing ALKBH3 mRNA association with polysomes to enhance its translation. This upregulation led to higher ALKBH3 protein levels, which is crucial for inhibiting gastric cancer cell proliferation. In contrast, when PUS7 is downregulated, ALKBH3 mRNA shows decreased association with polysomes. It showed that the translation of ALKBH3 mRNA was reduced and resulted in lower protein levels that favour cancer progression.
Increased levels of ALKBH3 were linked to the suppression of gastric cancer cell growth, invasion, and metastasis. This reflected that ALKBH3 can act as a tumour suppressor by decreasing cancer cell proliferation. The findings underlined that pseudouridylation is critical for its tumour-suppressive effects in gastric cancer.
Helicobacter pylori‐enhanced hnRNPA2B1 coordinates with PABPC1 to promote non‐m⁶A translation and gastric cancer progression
Advanced Science, 2024
Yu, Y., Yang, Y.L., Chen, X.Y., Chen, Z.Y., Zhu, J.S. and Zhang, J.
Helicobacter pylori (H. pylori) is a bacterium linked to gastric inflammation and cancer by promoting cancer at the molecular level. It also drives the expression of an RNA-binding protein, hnRNPA2B1 that drives the translation of specific mRNAs crucial for cancer progression. hnRNPA2B1 coordinates with poly(A)-binding protein cytoplasmic 1 (PABPC1) in this process.
The authors found that this interaction observed the bypassing of typical m⁶A-dependent pathway and was independent of m⁶A modification. Polysome profiling was used to analyse the translational landscape in gastric cancer cells influenced by H. pylori. It revealed that hnRNPA2B1 and PABPC1 formed a complex that selectively bound and stabilised non-m⁶A mRNAs in the polysomes. The complex enhanced the translation of the key genes that drive tumour growth. The increased expression of hnRNPA2B1 can also reduce chemosensitivity.
Overall, H. pylori activated the non-m⁶A translational pathway to promote gastric cancer development. This finding expanded the understanding of how bacterial infections can hijack host cellular mechanisms to promote cancer, opening avenues for treatments targeting hnRNPA2B1 and PABPC1 interactions.
SMYD5 methylation of rpL40 links ribosomal output to gastric cancer
Nature, 2024
Park, J., Wu, J., Szkop, K.J., Jeong, J., Jovanovic, P., Husmann, D., Flores, N.M., Francis, J.W., Chen, Y.J.C., Benitez, A.M., Zahn, E., Song, S., Ajani, J.A., Wang, L., Singh, K., Larsson, O., Garcia, B.A., Topisirovic, I., Gozani, O. and Mazur, P.K.
SMYD5 is a lysine methyltransferase that regulates ribosomal activity and promotes gastric adenocarcinoma (GAC) progression. SMYD5 methylates ribosomal protein L40 (rpL40), a component of the 60S ribosomal subunit, affecting protein synthesis. Its methylation improves ribosome biogenesis and function, and elevates translation of tumour-related proteins.
Focusing on the ribosome dynamics and protein synthesis, the authors revealed a direct connection between ribosomal modification and cancer progression. In gastric cancer cells, polysome profiling indicated that the increased SMYD5 expression elevated rpL40 methylation and subsequent upregulation of cancer-associated protein synthesis. SMYD5-mediated rpL40 methylation enhanced the cellular ability to produce proteins that support malignancy. This indicated that SMYD5 can drive oncogenic translation in gastric cancer.
SMYD5 methylated rpL40 at K22, which regulates protein synthesis at the mRNA translation level. The depletion of SMYD5 or mutation of rpL40K22 reduced protein synthesis, affecting GAC development. Elevated SMYD5 and rpL40K22me3 levels correlated with advanced GAC, suggesting their potential as biomarkers and therapeutic targets. SMYD5 inhibitors showed promise for combination cancer therapies with minimal toxicity.
The findings broadened the understanding of how translational control mechanisms contribute to cancer, offering a new perspective on gastric cancer treatment through modulation of ribosomal function and ribosome-associated protein methylation.