Genome-wide analysis of Chinese keloid patients identifies novel causative genes

Zhu, Yonglin; Zhou, Naihui; Xu, Yuhong; Liu, Ke; Li, Wei; Shi, Li-Yan; Hu, Yin-Xi; Xie, Yun; Lan, Jing; Yu, Zheng-Yuan

doi:10.21037/atm-22-1303

Cited by 3 publications

(5 citation statements)

References 40 publications

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“…This concords with our and other observations. Nitrotyrosine (reviews: [37][38][39][40][41][50][51][52][53]) and TTLL12 [11,[14][15][16][17][18][19] levels increase with tumour progression, suggesting that they are linked. However, the comparison is indirect, since this nitrotyrosine is mainly found in proteins as a result of chemical modification during oxidative and nitrosative stress, rather than as free nitrotyrosine that is required for ligation to the C-terminus of detyrosinated α-tubulin.…”

Section: Discussionmentioning

confidence: 99%

“…This overexpression in cancer could generate serum autoantibodies that recognise TTLL12 specifically in prostate cancer patients [13]. TTLL12 expression and alterations have been linked to prognosis of various cancers, including prostate [14], stomach [15], lung adenocarcinoma [16], ulcerative colitis [17], ovarian cancer [18], and keloids in Chinese patients [19]. A novel transcript isoform has been identified in human cancers [20].…”

Section: Introductionmentioning

confidence: 99%

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TTLL12 has a potential oncogenic activity, suppression of ligation of nitrotyrosine to the C-terminus of detyrosinated α-tubulin, that can be overcome by molecules identified by screening a compound library

Deshpande,

Brants,

Wasylyk

et al. 2024

PLoS ONE

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Tubulin tyrosine ligase 12 (TTLL12) is a promising target for therapeutic intervention since it has been implicated in tumour progression, the innate immune response to viral infection, ciliogenesis and abnormal cell division. It is the most mysterious of a fourteen-member TTL/TTLL family, since, although it is the topmost conserved in evolution, it does not have predicted enzymatic activities. TTLL12 seems to act as a pseudo-enzyme that modulates various processes indirectly. Given the need to target its functions, we initially set out to identify a property of TTLL12 that could be used to develop a reliable high-throughput screening assay. We discovered that TTLL12 suppresses the cell toxicity of nitrotyrosine (3-nitrotyrosine) and its ligation to the C-terminus of detyrosinated α-tubulin (abbreviated to ligated-nitrotyrosine). Nitrotyrosine is produced by oxidative stress and is associated with cancer progression. Ligation of nitrotyrosine has been postulated to be a check-point induced by excessive cell stress. We found that the cytotoxicities of nitrotyrosine and tubulin poisons are independent of one another, suggesting that drugs that increase nitrotyrosination could be complementary to current tubulin-directed therapeutics. TTLL12 suppression of nitrotyrosination of α-tubulin was used to develop a robust cell-based ELISA assay that detects increased nitrotyrosination in cells that overexpress TTLL12 We adapted it to a high throughput format and used it to screen a 10,000 molecule World Biological Diversity SETTM collection of low-molecular weight molecules. Two molecules were identified that robustly activate nitrotyrosine ligation at 1 μM concentration. This is the pioneer screen for molecules that modulate nitrotyrosination of α-tubulin. The molecules from the screen will be useful for the study of TTLL12, as well as leads for the development of drugs to treat cancer and other pathologies that involve nitrotyrosination.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TTLL12 has a potential oncogenic activity, suppression of ligation of nitrotyrosine to the C-terminus of detyrosinated α-tubulin, that can be overcome by molecules identified by screening a compound library

Deshpande,

Brants,

Wasylyk

et al. 2024

PLoS ONE

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show abstract

“…This concords with our and other observations. Nitrotyrosine [reviews: (37) (38)](39-41, 49-52) and TTLL12 (11, 14-19) levels increase with tumour progression, suggesting that they are linked. However, the comparison is indirect, since this nitrotyrosine is mainly found in proteins as a result of chemical modification during oxidative and nitrosative stress, rather than as free nitrotyrosine that is required for ligation to the C-terminus of detyrosinated α-tubulin.…”

Section: Discussionmentioning

confidence: 99%

“…This overexpression in cancer could generate serum autoantibodies that recognise TTLL12 specifically in prostate cancer patients (13). TTLL12 expression and alterations have been linked to prognosis of various cancers, including prostate (14), stomach (15), lung adenocarcinoma (16), ulcerative colitis (17), ovarian cancer (18), and keloids in Chinese patients (19). A novel transcript isoform has been identified in human cancers (20).…”

Section: Introductionmentioning

confidence: 99%

Novel inhibitors of TTLL12’s oncogenic potential that overcome suppression of ligation of nitrotyrosine to the C-terminus of detyrosinated α-tubulin

Deshpande,

Brants,

Wasylyk

et al. 2023

Preprint

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Tubulin tyrosine ligase 12 (TTLL) is a promising target for therapeutic intervention since it has been implicated in tumour progression, the innate immune response to viral infection, ciliogenesis and abnormal cell division. It is the most mysterious of a fourteen-member TTL/TTLL family, since, although it is the topmost conserved in evolution, it does not have predicted enzymatic activities. TTLL12 seems to act as a pseudo-enzyme that modulates various processes indirectly. Given the need to target its functions, we initially set out to identify a property of TTLL12 that could be used to develop a reliable high-throughput screening assay. We discovered that TTLL12 suppresses the cell toxicity of nitrotyrosine (3-nitrotyrosine) and its ligation to the C-terminus of detyrosinated α-tubulin (abbreviated to ligated-nitrotyrosine). Nitrotyrosine is produced by oxidative stress and is associated with cancer progression. Ligation of nitrotyrosine has been postulated to be a check-point induced by excessive cell stress. We found that the cytotoxicities of nitrotyrosine and tubulin poisons are independent of one another, suggesting that drugs that increase nitrotyrosination could be complementary to current tubulin-directed therapeutics. TTLL12 suppression of nitrotyrosination of α-tubulin was used to develop a robust cell-based ELISA assay that detects increased nitrotyrosination in cells that overexpress TTLL12 We adapted it to a high throughput format and used it to screen a 10,000 molecule World Biological Diversity SETTMcollection of low-molecular weight molecules. Two molecules were identified that robustly activate nitrotyrosine ligation at 1 μM concentration. This is the pioneer screen for molecules that modulate nitrotyrosination of α-tubulin. The molecules from the screen will be useful for the study of TTLL12, as well as leads for the development of drugs to treat cancer and other pathologies that involve nitrotyrosination.

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“…Currently, breast cancer is classified into different molecular subtypes, which have great significance for individualized intervention and prognostic prediction (2,28,29). Different molecular subtypes were also associated with anti-tumor treatment resistance in advanced cancers (30)(31)(32). In our study, we divided patients into 4 molecular subtypes based on the expression of HR and HER2 status as described above.…”

Section: Discussionmentioning

confidence: 99%

The ctDNA-based postoperative molecular residual disease status in different subtypes of early-stage breast cancer

Yang¹,

Zhang²,

Li³

et al. 2022

Gland Surg

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Background: Breast cancer is a highly heterogeneous disease. Early-stage, non-metastatic breast cancer is considered curable after definitive treatment. Early detection of tumor recurrence and metastasis through sensitive biomarkers is helpful for guiding clinical decision-making and early intervention in second-line treatment, which could improve patient prognosis and survival.Methods: In this real-world study, we retrospectively analyzed 82 patients with stages I to III breast cancer who had been analyzed by molecular residual disease (MRD) assay. A total of 82 tumor tissues and 224 peripheral blood samples were collected and detected by next-generation sequencing (NGS) based on a 1,021-gene panel in this study.Results: MRD positivity was detected in 18 of 82 patients (22.0%). The hormone receptor−/human epidermal growth factor receptor 2+ (HR−/HER2+) subgroup had the highest postoperative MRD detection rate at 30.8% (4/13). The BRCA2 and SLX4 genes were significantly enriched in all patients in the MRD positive group and FGFR1 amplification was significantly enriched in the MRD negative group with HR+/ HER2−. The number of single nucleotide variants (SNVs) in tissue samples of MRD-positive patients was higher than that of MRD-negative patients (11.94 vs. 8.50 SNVs/sample). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that there was a similar biological function of the tumormutated genes in the 2 MRD status groups.Conclusions: This real-world study confirmed that patient samples of primary tumor tissue with different MRD status and molecular subtypes had differential genetic features, which may be used to predict patients at high risk for recurrence.

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Genome-wide analysis of Chinese keloid patients identifies novel causative genes

Cited by 3 publications

References 40 publications

TTLL12 has a potential oncogenic activity, suppression of ligation of nitrotyrosine to the C-terminus of detyrosinated α-tubulin, that can be overcome by molecules identified by screening a compound library

TTLL12 has a potential oncogenic activity, suppression of ligation of nitrotyrosine to the C-terminus of detyrosinated α-tubulin, that can be overcome by molecules identified by screening a compound library

Novel inhibitors of TTLL12’s oncogenic potential that overcome suppression of ligation of nitrotyrosine to the C-terminus of detyrosinated α-tubulin

The ctDNA-based postoperative molecular residual disease status in different subtypes of early-stage breast cancer

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