PRMT5 Inhibition Promotes PD-L1 Expression and Immuno-Resistance in Lung Cancer

Hu, Rui; Zhou, Bingqian; Chen, Zheyi; Chen, Shiyu; Chen, Ningdai; Shen, Lisong; Xiao, Haibo; Zheng, Yingxia

doi:10.3389/fimmu.2021.722188

Cited by 26 publications

(18 citation statements)

References 26 publications

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“…PRMT5 is another known regulator of oncogenic development through its ability to regulate p53 pathway signaling and to drive the proliferative, invasive, and metastatic activity of tumor cells. [ 20 ] SF3B2 has been linked to a range of cancers such as pancreatic adenocarcinoma, renal cell carcinoma, and papillary carcinoma. Homozygous PRMT9 mutations may result in abnormal transcript slicing, disordered transcriptional regulation, and consequent changes in cellular function that can result in pro-tumorigenic proliferation and migration.…”

Section: Discussionmentioning

confidence: 99%

Identification of THSD7B and PRMT9 mutations as risk factors for familial lung adenocarcinoma: A case report

et al. 2023

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Rationale: Lung tumors arise from the unrestrained malignant growth of pulmonary epithelial cells. Lung cancer cases include both small and non-small cell lung cancers, with lung adenocarcinoma (LUAD) accounting for roughly half of all non-small cell lung cancer cases. Research focused on familial cancers suggests that approximately 8% of lung cancer cases are linked to genetic susceptibility or heritability. The precise genetic factors that underlie the onset of lung cancer, however, remain to be firmly established. Patient concerns: A 43-year-old presented with nodules in the lower left lung lobe. Following initial antibiotic treatment in a local hospital, these nodules remained present and the patient subsequently underwent the resection of the left lower lobe of the lung. The patient also had 4 family members with a history of LUAD. Diagnosis: Immunohistochemical staining results including cytokeratin 7 (+), TTF-1 (+), new aspartic proteinase A (+), CK5/6 (−), P63 (−), and Ki-67 (5%+) were consistent with a diagnosis of LUAD. Intervention: Whole exome sequencing analyses of 5 patients and 6 healthy family members were performed to explore potential mutations associated with familial LUAD. Outcomes: Whole exome sequencing was conducted, confirming that the proband and their 4 other family members with LUAD harbored heterozygous THSD7B (c.A4000G:p.S1334G) mutations and homozygous PRMT9 (c.G40T:p.G14C) mutations, as further confirmed via Sanger sequencing. These mutations were predicted to be deleterious using the SIFT, PolyPhen2, and MutationTaster algorithms. Protein structure analyses indicated that the mutation of the serine at amino acid position 1334 in THSD7B to a glycine would reduce the minimum free energy from 8.08 kcal/mol to 68.57 kcal/mol. The identified mutation in the PRMT9 mutation was not present in the predicted protein structure. I-Mutant2.0 predictions indicated that both of these mutations (THSD7B:p.S1334G and PRMT9: p.G14C) were predicted to reduce protein stability. Lessons: Heterozygous THSD7B (c.A4000G:p.S1334G) and the homozygous PRMT9 (c.G40T:p.G14C) mutations were found to be linked to LUAD incidence in the analyzed family. Early analyses of these genetic loci and timely genetic counseling may provide benefits and aid in the early diagnosis of familial LUAD.

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Section: Discussionmentioning

confidence: 99%

Identification of THSD7B and PRMT9 mutations as risk factors for familial lung adenocarcinoma: A case report

et al. 2023

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“…PD-L1 is a key molecule highly expressed in tumor cells that interacts with immune cells to constitute an immunosuppressive environment. In lung cancer, GSK591 drug inhibits PRMT5-induced PD-L1 expression, which then trigger immune resistance ( 85 ). Thus, the combination with PD-1 treatment and inhibition and elimination of PRMT5 may promote synergistic inhibition.…”

Section: Classification and Biological Functions Of Histone Methyltra...mentioning

confidence: 99%

The role of histone methylase and demethylase in antitumor immunity: A new direction for immunotherapy

Zhang

Chen²,

Liu³

et al. 2023

Front. Immunol.

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Epigenetic modifications may alter the proliferation and differentiation of normal cells, leading to malignant transformation. They can also affect normal stimulation, activation, and abnormal function of immune cells in the tissue microenvironment. Histone methylation, coordinated by histone methylase and histone demethylase to stabilize transcription levels in the promoter area, is one of the most common types of epigenetic alteration, which gained increasing interest. It can modify gene transcription through chromatin structure and affect cell fate, at the transcriptome or protein level. According to recent research, histone methylation modification can regulate tumor and immune cells affecting anti-tumor immune response. Consequently, it is critical to have a thorough grasp of the role of methylation function in cancer treatment. In this review, we discussed recent data on the mechanisms of histone methylation on factors associated with immune resistance of tumor cells and regulation of immune cell function.

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“…However, the phase I trial of type I PRMT inhibitor GSK3368715 has been terminated in part due to serious adverse events. Several defects of PRMT5 inhibitors have also emerged in preclinical studies, such as resistance in triple-negative breast cancer cells [ 195 ] and suppression of immune response [ 196 , 197 , 198 ]. Since PRMTs are crucial regulators of DDR, targeting DDR can be a potential strategy for enhancing the anti-tumor efficacy of PRMT inhibitors to achieve better outcomes ( Table 2 ).…”

Section: Synergistic Effects Of Prmt and Ddrmentioning

confidence: 99%

The Role of Protein Arginine Methyltransferases in DNA Damage Response

Brobbey

Liu

Yin

et al. 2022

IJMS

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In response to DNA damage, cells have developed a sophisticated signaling pathway, consisting of DNA damage sensors, transducers, and effectors, to ensure efficient and proper repair of damaged DNA. During this process, posttranslational modifications (PTMs) are central events that modulate the recruitment, dissociation, and activation of DNA repair proteins at damage sites. Emerging evidence reveals that protein arginine methylation is one of the common PTMs and plays critical roles in DNA damage response. Protein arginine methyltransferases (PRMTs) either directly methylate DNA repair proteins or deposit methylation marks on histones to regulate their transcription, RNA splicing, protein stability, interaction with partners, enzymatic activities, and localization. In this review, we summarize the substrates and roles of each PRMTs in DNA damage response and discuss the synergistic anticancer effects of PRMTs and DNA damage pathway inhibitors, providing insight into the significance of arginine methylation in the maintenance of genome integrity and cancer therapies.

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PRMT5 Inhibition Promotes PD-L1 Expression and Immuno-Resistance in Lung Cancer

Cited by 26 publications

References 26 publications

Identification of THSD7B and PRMT9 mutations as risk factors for familial lung adenocarcinoma: A case report

Identification of THSD7B and PRMT9 mutations as risk factors for familial lung adenocarcinoma: A case report

The role of histone methylase and demethylase in antitumor immunity: A new direction for immunotherapy

The Role of Protein Arginine Methyltransferases in DNA Damage Response

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