Search

The WD‐repeat (WDR) family affects carcinogenesis, but its role in the immune microenvironment is poorly characterized. Although functional loss or gain of WDR6 does not markedly change in vitro proliferative and invasive capacity of HCC cells, its deficiency in hepa1‐6 cells drastically inhibits the growth and lung metastasis of orthotopically implanted tumors in immune‐competent C57BL/6J mice. Mechanistically, WDR6 targets tumor suppressor UVRAG to the CUL4A‐DDB1‐ROC1 E3 ubiquitin ligase complex through a unique WDxR motif and promotes its degradation. This upregulates chromatin accessibility at the TNFα locus by blocking autophagic degradation of p65, elevates intratumoral myeloid‐derived suppressor cell (MDSC) number, and reduces CD8+ T cell infiltration, thereby promoting HCC progression. These immunosuppressive effects are reversed by TNFα blockade. TNFα recruits NF‐κB to activate the transcription of WDR6, establishing a WDR6‐TNFα loop. Clinically, the WDR6/UVRAG/NF‐κB pathway is hyperactivated in HCC, predicting a poor prognosis. Importantly, a WDxR‐like peptide disrupts the WDR6/UVRAG complex and enhances the efficiency of anti‐PD‐L1 against HCC with WDR6 dysregulation. Synopsis: The WD‐repeat (WDR) family affects carcinogenesis, but its role in immune microenvironment is poorly characterized. This study reports the cellular and molecular effects of targeting WDR6 on HCC. Functional loss of WDR6 inhibited HCC growth and metastasis only in immune‐competent mice.Increased number of intra‐tumoral PMN‐MDSCs mediated by WDR6 activation was reversed by TNFα blockade.UVRAG degradation was enhanced by WDR6 via a WDxR motif, thereby leading to TNFα increase and PMN‐MDSC recruitment in HCC.Anti‐PD‐L1 immunotherapy efficiency was improved by a WDxR‐like peptide in HCC with WDR6 dysregulation. [ABSTRACT FROM AUTHOR]

Abstract The WD‐repeat (WDR) family affects carcinogenesis, but its role in the immune microenvironment is poorly characterized. Although functional loss or gain of WDR6 does not markedly change in vitro proliferative and invasive capacity of HCC cells, its deficiency in hepa1‐6 cells drastically inhibits the growth and lung metastasis of orthotopically implanted tumors in immune‐competent C57BL/6J mice. Mechanistically, WDR6 targets tumor suppressor UVRAG to the CUL4A‐DDB1‐ROC1 E3 ubiquitin ligase complex through a unique WDxR motif and promotes its degradation. This upregulates chromatin accessibility at the TNFα locus by blocking autophagic degradation of p65, elevates intratumoral myeloid‐derived suppressor cell (MDSC) number, and reduces CD8+ T cell infiltration, thereby promoting HCC progression. These immunosuppressive effects are reversed by TNFα blockade. TNFα recruits NF‐κB to activate the transcription of WDR6, establishing a WDR6‐TNFα loop. Clinically, the WDR6/UVRAG/NF‐κB pathway is hyperactivated in HCC, predicting a poor prognosis. Importantly, a WDxR‐like peptide disrupts the WDR6/UVRAG complex and enhances the efficiency of anti‐PD‐L1 against HCC with WDR6 dysregulation.

Background: WD repeat domain 6 (WDR6), a novel human WD‐repeat gene, encodes a member of the WD repeat protein family, and its tumorigenic effect has rarely been reported so far. Methods: Our study used Oncomine, TIMER2.0, GEPIA2, Kaplan–Meier plotter, PrognoScan, and TISIDB tools to analyze the differential expression between pan‐cancer, especially lung cancer, and corresponding normal tissue, and further explore the prognostic and immunological role of WDR6 expression. Results: Our results showed WDR6 was lower expressed in lung squamous cell carcinoma than in normal tissue, but WDR6 expression was correlated obviously with clinical stage in Lung adenocarcinoma. The overall survival, first progression, postprogression survival, and Relapse‐free survival of lung cancer patients were longer in the WDR6 high‐expression group than in the low‐expression group. We found the expression of WDR6 significantly correlated with immune molecules, including immunomodulators, lymphocytes, and chemokines in lung cancer. Conclusion: WDR6 can be used as a prognostic marker for lung cancer and is significantly associated with immune cell infiltration. [ABSTRACT FROM AUTHOR]

Abstract Background WD repeat domain 6 (WDR6), a novel human WD‐repeat gene, encodes a member of the WD repeat protein family, and its tumorigenic effect has rarely been reported so far. Methods Our study used Oncomine, TIMER2.0, GEPIA2, Kaplan–Meier plotter, PrognoScan, and TISIDB tools to analyze the differential expression between pan‐cancer, especially lung cancer, and corresponding normal tissue, and further explore the prognostic and immunological role of WDR6 expression. Results Our results showed WDR6 was lower expressed in lung squamous cell carcinoma than in normal tissue, but WDR6 expression was correlated obviously with clinical stage in Lung adenocarcinoma. The overall survival, first progression, postprogression survival, and Relapse‐free survival of lung cancer patients were longer in the WDR6 high‐expression group than in the low‐expression group. We found the expression of WDR6 significantly correlated with immune molecules, including immunomodulators, lymphocytes, and chemokines in lung cancer. Conclusion WDR6 can be used as a prognostic marker for lung cancer and is significantly associated with immune cell infiltration.

tRNA modifications at the anti‐codon loop are critical for accurate decoding. FTSJ1 was hypothesized to be a human tRNA 2′‐O‐methyltransferase. tRNAPhe(GAA) from intellectual disability patients with mutations in ftsj1 lacks 2′‐O‐methylation at C32 and G34 (Cm32 and Gm34). However, the catalytic activity, RNA substrates, and pathogenic mechanism of FTSJ1 remain unknown, owing, in part, to the difficulty in reconstituting enzymatic activity in vitro. Here, we identify an interacting protein of FTSJ1, WDR6. For the first time, we reconstitute the 2′‐O‐methylation activity of the FTSJ1‐WDR6 complex in vitro, which occurs at position 34 of specific tRNAs with m1G37 as a prerequisite. We find that modifications at positions 32, 34, and 37 are interdependent and occur in a hierarchical order in vivo. We also show that the translation efficiency of the UUU codon, but not the UUC codon decoded by tRNAPhe(GAA), is reduced in ftsj1 knockout cells. Bioinformatics analysis reveals that almost 40% of the high TTT‐biased genes are related to brain/nervous functions. Our data potentially enhance our understanding of the relationship between FTSJ1 and nervous system development. Synopsis: FTSJ1, an intellectual disability associated protein, is the human cytoplasmic tRNA 32 and 34 2′‐O‐methyltransfearse that interacts with auxiliary protein WDR6 to catalyze Nm34 formation. Knockout of ftsj1 affects the translation efficiency of UUU codon usage biased genes. First successful reconstitution of the enzymatic activity of FTSJ1 in vitro.Modifications at positions 32, 34, and 37 on tRNA are interdependent and occur in a hierarchical order: (i) m1G37, (ii) Cm32 and Gm34, and (iii) o2yW37 formation from m1G.The translation efficiency of the UUU codon but not the UUC codon decoded by tRNAPhe(GAA) is reduced in ftsj1 knockout cells.Approximately 40% of the high TTT‐biased genes in human are related to brain/nervous functions. [ABSTRACT FROM AUTHOR]

Background: WD repeat domain 6 (WDR6), a novel human WD-repeat gene, encodes a member of the WD repeat protein family, and its tumorigenic effect has rarely been reported so far., Methods: Our study used Oncomine, TIMER2.0, GEPIA2, Kaplan-Meier plotter, PrognoScan, and TISIDB tools to analyze the differential expression between pan-cancer, especially lung cancer, and corresponding normal tissue, and further explore the prognostic and immunological role of WDR6 expression., Results: Our results showed WDR6 was lower expressed in lung squamous cell carcinoma than in normal tissue, but WDR6 expression was correlated obviously with clinical stage in Lung adenocarcinoma. The overall survival, first progression, postprogression survival, and Relapse-free survival of lung cancer patients were longer in the WDR6 high-expression group than in the low-expression group. We found the expression of WDR6 significantly correlated with immune molecules, including immunomodulators, lymphocytes, and chemokines in lung cancer., Conclusion: WDR6 can be used as a prognostic marker for lung cancer and is significantly associated with immune cell infiltration., (© 2022 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Disruptive epigenetic gene control has been shown to be involved in carcinogenesis. To identify key molecules in piperonyl butoxide (PBO)-induced hepatocarcinogenesis, we searched hypermethylated genes using CpG island (CGI) microarrays in non-neoplastic liver cells as a source of proliferative lesions at 25 weeks after tumor promotion with PBO using mice. We further performed methylation-specific polymerase chain reaction (PCR), real-time reverse transcription PCR, and immunohistochemical analysis in PBO-promoted liver tissues. Ebp4.1, Wdr6 and Cmtm6 increased methylation levels in the promoter region by PBO promotion, although Cmtm6 levels were statistically non-significant. These results suggest that PBO promotion may cause altered epigenetic gene regulation in non-neoplastic liver cells surrounding proliferative lesions to allow the facilitation of hepatocarcinogenesis. Both Wdr6 and Cmtm6 showed decreased expression in non-neoplastic liver cells in contrast to positive immunoreactivity in the majority of proliferative lesions produced by PBO promotion. These results suggest that both Wdr6 and Cmtm6 were spared from epigenetic gene modification in proliferative lesions by PBO promotion in contrast to the hypermethylation-mediated downregulation in surrounding liver cells. Considering the effective detection of proliferative lesions, these molecules could be used as detection markers of hepatocellular proliferative lesions and played an important role in hepatocarcinogenesis., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)