Abstract
Posttranslational modifications (PTMs) of proteins, including chromatin modifiers, play crucial roles in the dynamic alteration of various protein properties and functions including stem-cell properties. However, the roles of Lymphoid-specific helicase (LSH), a DNA methylation modifier, in modulating stem-like properties in cancer are still not clearly clarified. Therefore, exploring PTMs modulation of LSH activity will be of great significance to further understand the function and activity of LSH. Here, we demonstrate that LSH is capable to undergo PTMs, including methylation and phosphorylation. The arginine methyltransferase PRMT5 can methylate LSH at R309 residue, meanwhile, LSH could as well be phosphorylated by MAPK1 kinase at S503 residue. We further show that the accumulation of phosphorylation of LSH at S503 site exhibits downregulation of LSH methylation at R309 residue, which eventually promoting stem-like properties in lung cancer. Whereas, phosphorylation-deficient LSH S503A mutant promotes the accumulation of LSH methylation at R309 residue and attenuates stem-like properties, indicating the critical roles of LSH PTMs in modulating stem-like properties. Thus, our study highlights the importance of the crosstalk between LSH PTMs in determining its activity and function in lung cancer stem-cell maintenance.
Highlights
Lung cancer remains the most common cancer and the top cause of cancer-related mortality worldwide in 2018 when both sexes are combined, with 2.1 million newly diagnosed cases (11.6% of the total cancer cases) and an estimated 1.8 million deaths.[1]
glutathione S-transferase (GST)-Lymphoid-specific helicase (LSH) expressed in E. coli pulled down Protein arginine methyltransferase 5 (PRMT5) with HA tag expressed in 293T cells. f Schematic representation of Flag-tagged human LSH truncation derivatives and IP analysis followed by an IB assay for interaction between full-length PRMT5 and LSH fragments
LSH amino acids 227–589 are vital for its interaction with PRMT5. g Schematic representation of the HA-tagged human PRMT5 fragments and IP analysis followed by IB assay for interaction between full-length LSH and PRMT5 truncation mutants
Summary
Lung cancer remains the most common cancer and the top cause of cancer-related mortality worldwide in 2018 when both sexes are combined, with 2.1 million newly diagnosed cases (11.6% of the total cancer cases) and an estimated 1.8 million deaths (a mortality rate of ~18.4%).[1]. To discover critical elements and molecular pathways that could be targeted for valid therapy, it is extremely urgent to understand molecular mechanisms and identify key factors that drive lung cancer pathogenesis. A large number of studies have shown that resistance to chemoradiotherapy in lung cancer cells could play a vitally important role in weakening the efficacy of chemoradiotherapy, eventually leading to recurrence after treatment and poor survival.[3,4] increasing emerging evidence has shown that there exists a small population of lung carcinoma cells, called lung cancer stem-like cells, that can survive radiotherapy and/or chemotherapy and potentially propagate the tumor.[5] numerous studies indicate that lung cancer stem cells are responsible for tumor propagation, metastasis, resistance to conventional therapy and tumor recurrence.[6,7] understanding the molecular pathways and identifying the key factors underlying the stemness properties of lung cancer cells may contribute significantly to the development of novel and effective therapeutic targets. While a number of stem cell-specific markers have been identified in lung cancer stem cells, such as CD166 and aldehyde dehydrogenase (ALDH), as well as ATP binding cassette subfamily G member 2 (ABCG2),[8,9] to date, valid therapy targeting the eradication of lung cancer stem cells remains a tough challenge
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