ALKBH5 promotes PD-L1-mediated immune escape through m6A modification of ZDHHC3 in glioma

Tang, Wenhui; Xu, Ningbo; Zhou, Jian; He, Zhenyan; Lenahan, Cameron; Wang, Chenyang; Ji, Huangyi; Liu, Boyang; Zou, Yujiao; Zeng, Huijun; Guo, Hongbo

doi:10.1038/s41420-022-01286-w

Cited by 34 publications

(21 citation statements)

References 41 publications

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“…We next explored potential key molecular targets for the inhibition of pancreatic cancer growth after knockdown of ZDHHC3. Previous studies have shown that ZDHHC3 palmitoylates PD-L1 to maintain its protein stability in colon cancer and gliomas [ 23 , 46 ]. We next sought to determine whether ZDHHC3 influences cancer immunity by regulating PD-L1 expression in pancreatic cancer cells.…”

Section: Resultsmentioning

confidence: 99%

RETRACTED ARTICLE: Palmitoyl transferases act as novel drug targets for pancreatic cancer

Lin

Liu

et al. 2023

J Transl Med

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Background Pancreatic adenocarcinoma (PAAD) is one of the most leading causes of cancer-related death across the world with the limited efficiency and response rate of immunotherapy. Protein S-palmitoylation, a powerful post-translational lipid modification, is well-known to regulate the stability and cellular distribution of cancer-related proteins, which is mediated by a family of 23 palmitoyl transferases, namely zinc finger Asp-His-His-Cys-type (ZDHHC). However, whether palmitoyl transferases can determine tumor progression and the efficacy of immunotherapy in PAAD remains unknown. Methods Bioinformatics methods were used to identify differential ZDHHCs expression in PAAD. A systematic pan-cancer analysis was conducted to assess the immunological role of ZDHHC3 using RNA sequencing data from The Cancer Genome Atlas database. In vivo Panc 02 subcutaneous tumor model validated the anti-tumor effect of knockdown of ZDHHC3 or intraperitoneal injection of 2-bromopalmitate (2-BP), a typical broad-spectrum palmitoyl transferases inhibitor. Furthermore, we explored therapeutic strategies with combinations of 2-BP with PD-1/PD-L1-targeted immunotherapy in C57BL/6 mice bearing syngeneic Panc 02 pancreatic tumors. Results ZDHHC enzymes were associated with distinct prognostic values of pancreatic cancer. We identified that ZDHHC3 expression promotes an immunosuppressive tumor microenvironment in PAAD. 2-BP suppressed pancreatic-tumor cell viability and tumor sphere-forming activities, as well as increased cell apoptosis in vitro, without affecting normal human pancreatic ductal epithelial cells. Furthermore, genetic inactivation of ZDHHC3 or intraperitoneal injection of 2-BP impeded tumor progression in Panc 02 pancreatic tumors with enhanced anti-tumor immunity. 2-BP treatment significantly enhanced the therapeutic efficacy of PD-1/PD-L1 inhibitors in Panc 02 pancreatic tumors. Conclusion This study revealed some ZDHHC enzyme genes for predicting the prognosis of pancreatic cancer, and demonstrated that ZDHHC3 plays a critical oncogenic role in pancreatic cancer progression, highlighting its potential as an immunotherapeutic target of pancreatic cancer. In addition, combination therapy of 2-BP and PD-1/PD-L1 achieved synergic therapy effects in a mouse model of pancreatic cancer.

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Section: Resultsmentioning

confidence: 99%

RETRACTED ARTICLE: Palmitoyl transferases act as novel drug targets for pancreatic cancer

Lin

Liu

et al. 2023

J Transl Med

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“…Considering the role of YTHDF2 as an m6A “reader,” we carried out MeRIP‐seq in NOZ cells to detect the distribution of m6A modification and found that most of the m6A peaks were highly enriched in the 3′‐UTR of mRNAs (Figure 5E). A motif search identified a consensus sequence motif, GGAC, within the m6A peak region (Figure 5F), which is consistent with previous findings 24,25 …”

Section: Resultssupporting

confidence: 90%

“…A motif search identified a consensus sequence motif, GGAC, within the m6A peak region (Figure 5F), which is consistent with previous findings. 24,25 To identify the potential target mRNAs directly bounded by YTHDF2, anti-YTHDF2 RIP-seq was then carried out in NOZ cells with two replicates, and a total of 1502 genes were obtained (Figure 5G). YTHDF2 primarily acts by selectively binding to m6A-modified mRNAs and mediating their deadenylation.…”

Section: Identification Of the Ythdf2 Downstream Target By Multi-omic...mentioning

confidence: 99%

YTHDF2 promotes gallbladder cancer progression and gemcitabine resistance via m6A‐dependent DAPK3 degradation

Bai,

Chen,

Zhang

et al. 2023

Cancer Science

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N6‐methyladenosine (m6A) is the most abundant internal modification in eukaryotic RNA and involved in the carcinogenesis of various malignancies. However, the functions and mechanisms of m6A in gallbladder cancer (GBC) remain unclear. In this study, we investigated the role and underlying mechanism of the RNA‐binding protein YT521‐B homology domain‐containing family protein 2 (YTHDF2), an m6A reader, in GBC. Herein, we detected that YTHDF2 was remarkably upregulated in GBC tissues compared to normal gallbladder tissues. Functionally, YTHDF2 overexpression promoted the proliferation, tumor growth, migration, and invasion of GBC cells while inhibiting the apoptosis in vitro and in vivo. Conversely, YTHDF2 knockdown induced opposite results. Mechanistically, we further investigated the underlying mechanism by integrating RNA immunoprecipitation sequencing (RIP‐seq), m6A‐modified RIP‐seq, and RNA sequencing, which revealed that death‐associated protein kinase 3 (DAPK3) is a direct target of YTHDF2. YTHDF2 binds to the 3′‐UTR of DAPK3 mRNA and facilitates its degradation in an m6A‐dependent manner. DAPK3 inhibition restores the tumor‐suppressive phenotype induced by YTHDF2 deficiency. Moreover, the YTHDF2/DAPK3 axis induces the resistance of GBC cells to gemcitabine. In conclusion, we reveal the oncogenic role of YTHDF2 in GBC, demonstrating that YTHDF2 increases the mRNA degradation of the tumor suppressor DAPK3 in an m6A‐dependent way, which promotes GBC progression and desensitizes GBC cells to gemcitabine. Our findings provide novel insights into potential therapeutic strategies for GBC.

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“…Studies have confirmed the significant correlation of ALKBH5 with PD‐L1 in clinical intrahepatic cholangiocarcinoma specimens research 73 . Further studies found that the knockdown of ALKBH5 promotes the m6A level of PD‐L1 and accelerates mRNA degradation of PD‐L1 in a YTHDF2‐dependent manner in glioma 74 . Interestingly, impairing the expression level of ALKBH5 decreases PD‐L1 not only in cancer cells but also in monocytes/macrophages, suggesting that ALKBH5 can manipulate PD‐L1 by influencing the tumor immune microenvironment.…”

Section: The M6a Rna Methylation In Pd‐l1mentioning

confidence: 61%

“…73 Further studies found that the knockdown of ALKBH5 promotes the m6A level of PD-L1 and accelerates mRNA degradation of PD-L1 in a YTHDF2-dependent manner in glioma. 74 Interestingly, impairing the expression level of ALKBH5 decreases PD-L1 not only in cancer cells but also in monocytes/macrophages, suggesting that ALKBH5 can manipulate PD-L1 by influencing the tumor immune microenvironment. However, the specific mechanism is still undefined.…”

Section: Erasermentioning

confidence: 98%

The regulation of N6‐methyladenosine modification in PD‐L1‐induced anti‐tumor immunity

Lin

et al. 2023

Immunol Cell Biol

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There is growing evidence that programmed death ligand‐1 (PD‐L1) has exciting therapeutic efficacy in hematological malignancy and partial solid tumors. However, many patients still face failure with the treatment of immune checkpoint blockade because of PD‐L1 expression regulation during transcription and post‐transcription processes, including N6‐methyladenosine (m6A). Similar to the epigenetic regulation in DNA and histones, recent research has revealed the essential regulation of m6A modification in RNA nuclear export, metabolism and translation. Recent studies have shown that m6A‐induced PD‐L1 expression emerges as one of the main reasons for the immunological alteration in this process and contributes to the failure of T cell‐induced anti‐tumor immunity. The results of preclinical studies demonstrate the potential of m6A‐targeted therapy in combination with immune checkpoint blockade. The comprehensive expression of m6A‐related genes also provided the possibility to indicate the prognosis and to optimize the treatment for patients of various cancer types. In this review, we focus on the m6A modification in PD‐L1 mRNA as well as the regulation of PD‐L1 expression in cancer cells and summarize its clinical value in anti‐PD‐L1 cancer immune therapy.

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ALKBH5 promotes PD-L1-mediated immune escape through m6A modification of ZDHHC3 in glioma

Cited by 34 publications

References 41 publications

RETRACTED ARTICLE: Palmitoyl transferases act as novel drug targets for pancreatic cancer

RETRACTED ARTICLE: Palmitoyl transferases act as novel drug targets for pancreatic cancer

YTHDF2 promotes gallbladder cancer progression and gemcitabine resistance via m6A‐dependent DAPK3 degradation

The regulation of N6‐methyladenosine modification in PD‐L1‐induced anti‐tumor immunity

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