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Purpose: Local recurrence predicts dismal prognosis in eyelid sebaceous carcinoma (SC). Recurrence predictors vary across studies. Accurate recurrence estimation is essential for individualized therapy in eyelid SC. This study aims to identify recurrence predictors and develop a nomogram for personalized prediction in eyelid SC. Methods: We conducted a multicenter retrospective cohort study. Chart reviews were performed in 418 consecutive patients with eyelid SC. All patients were followed up after their initial surgery. Multivariate Cox regression was used to explore the independent predictors of recurrence. A nomogram for recurrence prediction was developed and validated with bootstrap resampling. The predictive accuracy and discriminative ability were compared with the Tumor, Node, Metastasis (TNM) staging system. Results: Over a median of 60-month follow-up, 167 patients (40%) had local recurrence. The median time from diagnosis to recurrence was 14 months. The 1-year cumulative recurrence rate was 18%. Diagnostic delay (hazard ratio [HR] = 1.01, 95% confidence interval [CI] = 1.00-1.01, P = 0.001), orbital involvement (HR = 4.47, 95% CI = 3.04-6.58, P < 0.001), Ki67 (HR = 1.01, 95% CI = 1.00-1.02, P = 0.008) and initial surgery of Mohs micrographic surgery with intraoperative frozen section control (HR = 0.53, 95% CI = 0.35-0.80, P = 0.003) were independent influencing factors of recurrence. A nomogram integrating these four factors combined with pagetoid spread displayed satisfactory discriminative ability (C-index = 0.80-0.83; area under the curve [AUC] = 0.82-0.84), which compared favorably than TNM staging (all P < 0.05). Conclusions: The recurrence rate is high in eyelid SC. Early detection and primary resection with Mohs micrographic surgery are recommended in controlling recurrence. Patients with orbital involvement, high Ki67 expression, and pagetoid spread may require adjuvant measures. This nomogram offers more accurate recurrence estimates, aiding in therapeutic decision making.
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Adenocarcinoma Sebáceo , Neoplasias de los Párpados , Recurrencia Local de Neoplasia , Nomogramas , Neoplasias de las Glándulas Sebáceas , Humanos , Masculino , Femenino , Estudios Retrospectivos , Neoplasias de los Párpados/patología , Neoplasias de los Párpados/diagnóstico , Neoplasias de las Glándulas Sebáceas/patología , Neoplasias de las Glándulas Sebáceas/diagnóstico , Persona de Mediana Edad , Anciano , Adenocarcinoma Sebáceo/patología , Adenocarcinoma Sebáceo/diagnóstico , Estudios de Seguimiento , Estadificación de Neoplasias , Anciano de 80 o más Años , Adulto , PronósticoRESUMEN
Lactylation, a post-translational modification (PTM) induced by lactate, has crucial roles in the regulation of transcription, DNA repair, and mitochondrial metabolism. Here, we discuss the role of lactate/lactylation signaling in regulating eye morphogenesis and retinal homeostasis, as well as various ophthalmic disorders, such as myopia, intraocular malignancies, and retinal angiogenesis.
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Conjunctival melanoma (CoM) is a potentially devastating tumor that can lead to distant metastasis. Despite various therapeutic strategies for distant metastatic CoM, the clinical outcomes remain unfavorable. Herein, we performed single-cell RNA sequencing (scRNA-seq) of 47,017 cells obtained from normal conjunctival samples (n = 3) and conjunctival melanomas (n = 7). Notably, we noticed a higher abundance of cancer-associated fibroblasts (CAFs) in tumor microenvironment (TME), correlated with enhanced angiogenic capacity and increased VEGFR expression in distal metastatic CoM. Additionally, we observed a significant decrease in the proportion of total CD8+ T cells and an increase in the proportion of naive CD8+ T cells, contributing to a relatively quiescent immunological environment in distal metastatic CoM. These findings were confirmed through the analyses of 70,303 single-cell transcriptomes of 7 individual CoM samples, as well as spatially resolved proteomes of an additional 10 samples of CoMs. Due to the increase of VEGFR-mediated angiogenesis and a less active T cell environment in distal metastatic CoMs, a clinical trial (ChiCTR2100045061) has been initiated to evaluate the efficacy of VEGFR blockade in combination with anti-PD1 therapy for patients with distant metastatic CoM, showing promising tumor-inhibitory effects. In conclusion, our study uncovered the landscape and heterogeneity of the TME during CoM tumorigenesis and progression, empowering clinical decisions in the management of distal metastatic CoM. To our knowledge, this is the initial exploration to translate scRNA-seq analysis to a clinical trial dealing with cancer, providing a novel concept by accommodating scRNA-seq data in cancer therapy.
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Cancer-associated fibroblasts (CAFs) exhibit notable versatility, plasticity, and robustness, actively participating in cancer progression through intricate interactions within the tumor microenvironment (TME). N6-methyladenosine (m6A) modification is the most prevalent modification in eukaryotic mRNA, playing essential roles in mRNA metabolism and various biological processes. Howbeit, the precise involvement of m6A in CAF activation remains enigmatic. In this study, we revealed that the m6A demethylase FTO supports CAF-mediated angiogenesis through activation of EGR1 and VEGFA in conjunctival melanoma (CoM). First, single-cell transcriptome analysis revealed that FTO was specifically upregulated in the CAF population, thereby contributing to the hypo-m6A status in the TME of CoM. Moreover, CAFs of CoM displayed extensive proangiogenic potential, which was largely compromised by FTO inhibition, both in vitro and in vivo. By employing multi-omics analysis, we showed that FTO effectively eliminates the m6A modifications of VEGFA and EGR1. This process subsequently disrupts the YTHDF2-dependent mRNA decay pathway, resulting in increased mRNA stability and upregulated expression of these molecules. Collectively, our findings initially indicate that the upregulation of FTO plays a pivotal role in tumor development by promoting CAF-mediated angiogenesis. Therapeutically, targeting FTO may show promise as a potential antiangiogenic strategy to optimize cancer treatment.
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Adenosina , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Fibroblastos Asociados al Cáncer , Proteína 1 de la Respuesta de Crecimiento Precoz , Neovascularización Patológica , Microambiente Tumoral , Factor A de Crecimiento Endotelial Vascular , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Humanos , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Animales , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Ratones , Estabilidad del ARN , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Melanoma/genética , Melanoma/patología , Melanoma/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Inductores de la Angiogénesis/metabolismoRESUMEN
Retinoblastoma, the primary ocular malignancy in pediatric patients, poses a substantial threat to mortality without prompt and effective management. The prognosis for survival and preservation of visual acuity hinges upon the disease severity at the time of initial diagnosis. Notably, retinoblastoma has played a crucial role in unraveling the genetic foundations of oncogenesis. The process of tumorigenesis commonly begins with the occurrence of biallelic mutation in the RB1 tumor suppressor gene, which is then followed by a cascade of genetic and epigenetic alterations that correspond to the clinical stage and pathological features of the tumor. The RB1 gene, recognized as a tumor suppressor, encodes the retinoblastoma protein, which plays a vital role in governing cellular replication through interactions with E2F transcription factors and chromatin remodeling proteins. The diagnosis and treatment of retinoblastoma necessitate consideration of numerous factors, including disease staging, germline mutation status, family psychosocial factors, and the resources available within the institution. This review has systematically compiled and categorized the latest developments in the diagnosis and treatment of retinoblastoma which enhanced the quality of care for this pediatric malignancy.
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Neoplasias de la Retina , Retinoblastoma , Retinoblastoma/terapia , Retinoblastoma/diagnóstico , Retinoblastoma/genética , Humanos , Neoplasias de la Retina/terapia , Neoplasias de la Retina/diagnóstico , Neoplasias de la Retina/genética , Manejo de la EnfermedadRESUMEN
Purpose: Acute retinal arterial ischemia diseases (ARAIDs) are ocular emergencies that require immediate intervention within a restricted therapeutic window to prevent blindness. However, the underlying molecular mechanisms contributing to the pathogenesis of ARAIDs remain enigmatic. Herein, we present the single-cell RNA sequencing (scRNA-seq) alterations during ischemia in the primate retina as a preliminary endeavor in understanding the molecular complexities of ARAIDs. Methods: An ophthalmic artery occlusion model was established through ophthalmic artery ligation in two Macaca fascicularis. scRNA-seq and bioinformatics analyses were used to detect retinal changes during ischemia, which are further validated by immunofluorescence analysis. Western blot and flow cytometry assays were performed to measure the microglia polarization status. Results: The findings of this study reveal notable changes in the retina under acute ischemic conditions. Particularly, retinal ischemia compromised mitochondrial functions of rod photoreceptors, partly leading to the rapid loss of healthy rods. Furthermore, we observed a noteworthy transcriptional alteration in the activation of microglia induced by ischemia. The targeted correction of the proinflammatory cytokine CXCL8 effectively suppresses microglia M1 polarization in retinal ischemia, ultimately reducing the proinflammatory transformation in vitro. In addition, retina ischemia induced the apoptotic inclination of endothelial cells and the heightened interaction with microglia, which signifies the influence of microglia in disrupting the retinal-blood barrier. Conclusions: Our research has successfully identified and described the pathologic alterations occurring in several cell types during a short period of ischemia. These observations provide valuable insights for ameliorating retinal damage and promoting the restoration of vision.
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Células Endoteliales , Enfermedades de la Retina , Animales , Macaca fascicularis , Células Endoteliales/metabolismo , Retina/metabolismo , Enfermedades de la Retina/patología , Microglía/metabolismo , Isquemia/metabolismo , Perfilación de la Expresión GénicaRESUMEN
Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a relatively uncommon autosomal-dominant genetic disorder, primarily attributed to mutations in the forkhead box L2 (FOXL2) gene. Albeit the involvement of protein-coding regions of FOXL2 has been observed in the majority of BPES cases, whether deficiencies in regulatory elements lead to the pathogenesis remains poorly understood. Herein, an autosomal-dominant BPES type II family was included. Peripheral venous blood has been collected, and genomic DNA has been extracted from leukocytes. A whole exome sequencing analysis has been performed and analyzed (Deposited in NODE database: OER422653). The promoter region of FOXL2 was amplified using polymerase chain reaction (PCR). The luciferase reporter assay was performed to identify the activity of this region. In this study, we present a Chinese family diagnosed with type II BPES, characterized by the presence of small palpebral fissures, ptosis, telecanthus, and epicanthus inversus. Notably, all male individuals within the family display polydactyly. A 225-bp deletion in the 556-bp 5'-upstream to transcription start site of FOXL2 , decorated by multiple histone modifications, was identified in affected members of the family. This deletion significantly decreased FOXL2 promoter activity, as measured by the luciferase assay. Conclusively, a novel 255-bp-deletion of the FOXL2 promoter was identified in Chinese families with BPES. Our results expand the spectrum of known FOXL2 mutations and provide additional insight into the genotype-phenotype relationships of the BPES pathogenesis. In addition, this study indicates the important role of genetic screening of cis-regulatory elements in testing heritable diseases.
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Blefarofimosis , Blefaroptosis , Anomalías Cutáneas , Anomalías Urogenitales , Humanos , Masculino , Proteína Forkhead Box L2/genética , Blefarofimosis/genética , Blefarofimosis/diagnóstico , Linaje , Mutación , Regiones Promotoras Genéticas/genética , China , Luciferasas/genéticaRESUMEN
Albeit N1-Methyladenosine (m1A) RNA modification represents an important regulator of RNA metabolism, the role of m1A modification in carcinogenesis remains enigmatic. Herein, we found that histone lactylation enhances ALKBH3 expression and simultaneously attenuates the formation of tumor-suppressive promyelocytic leukemia protein (PML) condensates by removing the m1A methylation of SP100A, promoting the malignant transformation of cancers. First, ALKBH3 is specifically upregulated in high-risk ocular melanoma due to excessive histone lactylation levels, referring to m1A hypomethylation status. Moreover, the multiomics analysis subsequently identified that SP100A, a core component for PML bodies, serves as a downstream candidate target for ALKBH3. Therapeutically, the silencing of ALKBH3 exhibits efficient therapeutic efficacy in melanoma both in vitro and in vivo, which could be reversed by the depletion of SP100A. Mechanistically, we found that YTHDF1 is responsible for recognition of the m1A methylated SP100A transcript, which increases its RNA stability and translational efficacy. Conclusively, we initially demonstrated that m1A modification is necessary for tumor suppressor gene expression, expanding the current understandings of dynamic m1A function during tumor progression. In addition, our results indicate that lactylation-driven ALKBH3 is essential for the formation of PML nuclear condensates, which bridges our knowledge of m1A modification, metabolic reprogramming, and phase-separation events.
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Dioxigenasa Dependiente de Alfa-Cetoglutarato, Homólogo 3 de AlkB , Antígenos Nucleares , Autoantígenos , Neoplasias del Ojo , Histonas , Melanoma , Humanos , Dioxigenasa Dependiente de Alfa-Cetoglutarato, Homólogo 3 de AlkB/metabolismo , Desmetilación , Metilación de ADN , Histonas/genética , Histonas/metabolismo , Proteína de la Leucemia Promielocítica/genética , Proteína de la Leucemia Promielocítica/metabolismo , ARN/metabolismo , Factores de Transcripción/metabolismo , Antígenos Nucleares/metabolismo , Autoantígenos/metabolismo , Neoplasias del Ojo/metabolismoRESUMEN
Purpose: Eyelid sebaceous carcinoma (SeC) is the third most frequent eyelid malignancy worldwide and is relatively prevalent in Asian patients. An eyelid SeC cell line model is necessary for experimental research to explore the etiology and pathogenesis of eyelid SeC. This study established and characterized an eyelid SeC cell line with a TP53 mutation that might be useful for analyzing potential treatment options for eyelid SeC. Methods: The eyelid SeC cell line SHNPH-SeC was obtained from a patient with eyelid SeC at Shanghai Ninth People's Hospital (SHNPH), Shanghai JiaoTong University School of Medicine. Immunofluorescence staining was employed to detect the origination and proliferation activity. Short tandem repeat (STR) profiling was performed for verification. Chromosome analysis was implemented to investigate chromosome aberrations. Whole exome sequencing (WES) was used to discover genomic mutations. Cell proliferation assays were performed to identify sensitivity to mitomycin-C (MMC) and 5-fluorouracil (5-FU). Results: SHNPH-SeC cells were successively subcultured for more than 100 passages and demonstrated rapid proliferation and migration. Karyotype analysis revealed abundant chromosome aberrations, and WES revealed SeC-related mutations in TP53, KMT2C, and ERBB2. An in vivo tumor model was successfully established in NOD/SCID mice. Biomarkers of eyelid SeC, including cytokeratin 5 (CK5), epithelial membrane antigen (EMA), adipophilin, p53, and Ki-67, were detected in SHNPH-SeC cells, original tumors, and xenografts. MMC and 5-FU inhibited the proliferation and migration of SHNPH-SeC cells, and SHNPH-SeC cells presented a greater drug response than non-TP53-mutated SeC cells. Conclusions: The newly established eyelid SeC cell line SHNPH-SeC demonstrates mutation in TP53, the most commonly mutated gene in SeC. It presents SeC properties and malignant characteristics that may facilitate the investigation of cellular behaviors and molecular mechanisms of SeC to explore promising therapeutic strategies.
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Adenocarcinoma Sebáceo , Carcinoma , Neoplasias de los Párpados , Neoplasias de las Glándulas Sebáceas , Neoplasias Cutáneas , Animales , Ratones , Humanos , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Ratones SCID , Ratones Endogámicos NOD , China , Adenocarcinoma Sebáceo/genética , Adenocarcinoma Sebáceo/diagnóstico , Adenocarcinoma Sebáceo/metabolismo , Aberraciones Cromosómicas , Línea Celular Tumoral , Párpados/patología , Neoplasias de los Párpados/genética , Neoplasias de los Párpados/diagnóstico , Neoplasias de los Párpados/metabolismo , Neoplasias de las Glándulas Sebáceas/genética , Neoplasias de las Glándulas Sebáceas/diagnóstico , Neoplasias de las Glándulas Sebáceas/metabolismo , Fluorouracilo/farmacologíaRESUMEN
Purpose: Retinoblastoma (RB) is a life-threatening malignancy that arises from the retina and is activated upon homozygous inactivation of the tumor suppressor RB1. Gene therapy targeting RB1 is an effective strategy to treat RB. However, it is difficult to target the RB1 gene by site-specific repair, with up to 3366 gene mutation sites identified in RB1. Thus, it is necessary to construct a promising and efficacious gene therapeutic strategy for patients with RB. Methods: To recover the function of the RB1 protein, we constructed a recombinant adeno-associated virus 2 (rAAV2) expressing RB1 that can restore RB1 function and significantly inhibit RB progression. To confirm the clinical feasibility of rAAV2-RB1, the RB1 protein was validated in vitro and in vivo after transfection. To further evaluate the clinical efficacy, RB patient-derived xenograft models were established and applied. The biosafety of rAAV2-RB1 was also validated in immunocompetent mice. Results: rAAV2-RB1 was a rAAV2 expressing the RB1 protein, which was validated in vitro and in vivo. In vitro, rAAV2-RB1 was effectively expressed in patient-derived RB cells. In mice, intravitreal administration of rAAV2-RB1 in a population-based patient-derived xenograft trial induced limited tumor growth. Moreover, after transfection of rAAV2-RB1 in immunocompetent mice, rAAV2-RB1 did not replicate and was expressed in other important organs, except retinas, inducing minor local side effects. Conclusions: Our study suggested a promising efficacy gene therapeutic strategy, which might provide a chemotherapy-independent treatment option for RB.
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Neoplasias de la Retina , Retinoblastoma , Humanos , Animales , Ratones , Retinoblastoma/genética , Retinoblastoma/terapia , Retinoblastoma/patología , Dependovirus/genética , Terapia Genética , Neoplasias de la Retina/genética , Neoplasias de la Retina/terapia , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas de Unión a Retinoblastoma/genéticaRESUMEN
BACKGROUND: Diversified histone deacetylation inhibitors (HDACis) have demonstrated encouraging outcomes in multiple malignancies. N6-methyladenine (m6 A) is the most prevalent messenger RNA modification that plays an essential role in the regulation of tumorigenesis. Howbeit, an in-depth understanding of the crosstalk between histone acetylation and m6 A RNA modifications remains enigmatic. This study aimed to explore the role of histone acetylation and m6 A modifications in the regulation of tumorigenesis of ocular melanoma. METHODS: Histone modification inhibitor screening was used to explore the effects of HDACis on ocular melanoma cells. Dot blot assay was used to detect the global m6 A RNA modification level. Multi-omics assays, including RNA-sequencing, cleavage under targets and tagmentation, single-cell sequencing, methylated RNA immunoprecipitation-sequencing (meRIP-seq), and m6 A individual nucleotide resolution cross-linking and immunoprecipitation-sequencing (miCLIP-seq), were performed to reveal the mechanisms of HDACis on methyltransferase-like 14 (METTL14) and FAT tumor suppressor homolog 4 (FAT4) in ocular melanoma. Quantitative real-time polymerase chain reaction (qPCR), western blotting, and immunofluorescent staining were applied to detect the expression of METTL14 and FAT4 in ocular melanoma cells and tissues. Cell models and orthotopic xenograft models were established to determine the roles of METTL14 and FAT4 in the growth of ocular melanoma. RNA-binding protein immunoprecipitation-qPCR, meRIP-seq, miCLIP-seq, and RNA stability assay were adopted to investigate the mechanism by which m6 A levels of FAT4 were affected. RESULTS: First, we found that ocular melanoma cells presented vulnerability towards HDACis. HDACis triggered the elevation of m6 A RNA modification in ocular melanoma. Further studies revealed that METTL14 served as a downstream candidate for HDACis. METTL14 was silenced by the hypo-histone acetylation status, whereas HDACi restored the normal histone acetylation level of METTL14, thereby inducing its expression. Subsequently, METTL14 served as a tumor suppressor by promoting the expression of FAT4, a tumor suppressor, in a m6 A-YTH N6-methyladenosine RNA-binding protein 1-dependent manner. Taken together, we found that HDACi restored the histone acetylation level of METTL14 and subsequently elicited METTL14-mediated m6 A modification in tumorigenesis. CONCLUSIONS: These results demonstrate that HDACis exert anti-cancer effects by orchestrating m6 A modification, which unveiling a "histone-RNA crosstalk" of the HDAC/METTL14/FAT4 epigenetic cascade in ocular melanoma.
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Histonas , Melanoma , Humanos , Metilación , Histonas/metabolismo , Histona Desacetilasas/metabolismo , Línea Celular Tumoral , Melanoma/genética , Carcinogénesis , ARN/metabolismo , Proteínas de Unión al ARN/genética , Metiltransferasas/genética , Metiltransferasas/metabolismoRESUMEN
BACKGROUND: The precise temporal and spatial regulation of N5 -methylcytosine (m5 C) RNA modification plays essential roles in RNA metabolism, and is necessary for the maintenance of epigenome homeostasis. Howbeit, the mechanism underlying the m5 C modification in carcinogenesis remains to be fully addressed. METHODS: Global and mRNA m5 C levels were determined by mRNA isolation and anti-m5 C dot blot in both retinoblastoma (RB) cells and clinical samples. Orthotopic intraocular xenografts were established to examine the oncogenic behaviours of RB. Genome-wide multiomics analyses were performed to identify the functional target of NSUN2, including proteomic analysis, transcriptome screening and m5 C-methylated RNA immunoprecipitation sequencing (m5 C-meRIP-seq). Organoid-based single-cell analysis and gene-correlation analysis were performed to verify the NSUN2/ALYREF/m5 C-PFAS oncogenic cascade. RESULTS: Herein, we report that NSUN2-mediated m5 C RNA methylation fuels purine biosynthesis during the oncogenic progression of RB. First, we discovered that global and mRNA m5 C levels were significantly enriched in RBs compared to normal retinas. In addition, tumour-specific NSUN2 expression was noted in RB samples and cell lines. Therapeutically, targeted correction of NSUN2 exhibited efficient therapeutic efficacy in RB both in vitro and in vivo. Through multiomics analyses, we subsequently identified phosphoribosylformylglycinamidine synthase (PFAS), a vital enzyme in purine biosynthesis, as a downstream candidate target of NSUN2. The reintroduction of PFAS largely reversed the inhibitory phenotypes in NSUN2-deficient RB cells, indicating that PFAS was a functional downstream target of NSUN2. Mechanistically, we found that the m5 C reader protein ALYREF was responsible for the recognition of the m5 C modification of PFAS, increasing its expression by enhancing its RNA stability. CONCLUSIONS: Conclusively, we initially demonstrated that NSUN2 is necessary for oncogenic gene activation in RB, expanding the current understanding of dynamic m5 C function during tumour progression. As the NSUN2/ALYREF/m5 C-PFAS oncogenic cascade is an important RB trigger, our study suggests that a targeted m5 C reprogramming therapeutic strategy may be a novel and efficient anti-tumour therapy approach.
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Neoplasias de la Retina , Retinoblastoma , Humanos , Metilación , Metiltransferasas/genética , Metiltransferasas/metabolismo , Proteómica , Retinoblastoma/genética , ARN/metabolismo , Estabilidad del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
The reversible and precise temporal and spatial regulation of histone lysine methyltransferases (KMTs) is essential for epigenome homeostasis. The dysregulation of KMTs is associated with tumor initiation, metastasis, chemoresistance, invasiveness, and the immune microenvironment. Therapeutically, their promising effects are being evaluated in diversified preclinical and clinical trials, demonstrating encouraging outcomes in multiple malignancies. In this review, we have updated recent understandings of KMTs' functions and the development of their targeted inhibitors. First, we provide an updated overview of the regulatory roles of several KMT activities in oncogenesis, tumor suppression, and immune regulation. In addition, we summarize the current targeting strategies in different cancer types and multiple ongoing clinical trials of combination therapies with KMT inhibitors. In summary, we endeavor to depict the regulation of KMT-mediated epigenetic landscape and provide potential epigenetic targets in the treatment of cancers.
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Retinoblastoma, the most prevalent primary intraocular tumor in children, leads to vision impairment, disability and even death. In addition to RB1 inactivation, MYCN activation has been documented as another common oncogenic alteration in retinoblastoma and represents one of the high-risk molecular subtypes of retinoblastoma. However, how MYCN contributes to the progression of retinoblastoma is still incompletely understood. Here, we report that MYCN upregulates YTHDF1, which encodes one of the reader proteins for N6-methyladenosine (m6A) RNA modification, in retinoblastoma. We further found that this MYCN-upregulated m6A reader functions to promote retinoblastoma cell proliferation and tumor growth in an m6A binding-dependent manner. Mechanistically, YTHDF1 promotes the expression of multiple oncogenes by binding to their mRNAs and enhancing mRNA stability and translation in retinoblastoma cells. Taken together, our findings reveal a novel MYCN-YTHDF1 regulatory cascade in controlling retinoblastoma cell proliferation and tumor growth, pinpointing an unprecedented mechanism for MYCN amplification and/or activation to promote retinoblastoma progression.
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Neoplasias de la Retina , Retinoblastoma , Niño , Humanos , Retinoblastoma/genética , Retinoblastoma/metabolismo , Retinoblastoma/patología , Proteína Proto-Oncogénica N-Myc/genética , Proteína Proto-Oncogénica N-Myc/metabolismo , Oncogenes , Neoplasias de la Retina/genética , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismoRESUMEN
Targeting programmed cell death protein ligand 1 (PD-L1) remains one of the most essential immunotherapies in cancer1,2. PD-L1 has been detected in the nucleus in multiple malignancies, playing an oncogenic role independent of immune checkpoint regulation3-5. Howbeit, the regulatory function of nuclear PD-L1 (nPD-L1) remains to be fully understood. Here, we report that nPD-L1 is an endogenous accelerator for cancer angiogenesis. First, we found that an abundant proportion of PD-L1 was distributed within the nucleus of uveal melanoma samples, which is associated with an unfavorable outcome. Moreover, the capacity of promoting angiogenesis was largely attenuated in the nPD-L1-deficient cells both in vivo and in vitro. Mechanistically, nPD-L1 facilitates p-STAT3 binding to the promoter of early growth response-1 (EGR1), resulting in the activation of EGR1-mediated angiogenesis. Therapeutically, the inhibition of histone deacetylase 2 restores the normal acetylation level of PD-L1, blocking its nuclear translocation and thereby attenuating tumor angiogenesis. Conclusively, we reveal that nPD-L1 promotes angiogenesis in malignancies, and provide a novel anti-vascularization strategy through blocking aberrant PD-L1 nuclear translocation for tumor therapy.
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Uveal melanoma (UM) is the most frequent and life-threatening ocular malignancy in adults. Aberrant histone methylation contributes to the abnormal transcriptome during oncogenesis. However, a comprehensive understanding of histone methylation patterns and their therapeutic potential in UM remains enigmatic. Herein, using a systematic epi-drug screening and a high-throughput transcriptome profiling of histone methylation modifiers, we observed that disruptor of telomeric silencing-1-like (DOT1L), a methyltransferase of histone H3 lysine 79 (H3K79), was activated in UM, especially in the high-risk group. Concordantly, a systematic epi-drug library screening revealed that DOT1L inhibitors exhibited salient tumor-selective inhibitory effects on UM cells, both in vitro and in vivo. Combining Cleavage Under Targets and Tagmentation (CUT&Tag), RNA sequencing (RNA-seq), and bioinformatics analysis, we identified that DOT1L facilitated H3K79 methylation of nicotinate phosphoribosyltransferase (NAPRT) and epigenetically activated its expression. Importantly, NAPRT served as an oncogenic accelerator by enhancing nicotinamide adenine dinucleotide (NAD+) synthesis. Therapeutically, DOT1L inhibition epigenetically silenced NAPRT expression through the diminishment of dimethylation of H3K79 (H3K79me2) in the NAPRT promoter, thereby inhibiting the malignant behaviors of UM. Conclusively, our findings delineated an integrated picture of the histone methylation landscape in UM and unveiled a novel DOT1L/NAPRT oncogenic mechanism that bridges transcriptional addiction and metabolic reprogramming.
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AIMS: To determine the distribution of three different intraepithelial growth patterns (pagetoid, bowenoid and papillary) in eyelid sebaceous carcinoma (SC) and correlate them with the clinical characteristics and prognosis. METHODS: A retrospective cohort study. The medical charts and pathological sections were retrospectively reviewed. All eligible patients were followed up for recurrence, metastasis and tumour-related mortality. The clinical significance of each intraepithelial growth pattern was determined by Cox regression. RESULTS: Of the 214 patients, 67 (31%) presented with intraepithelial invasion, among them, 34 (16%) were pagetoid, 27 (13%) were bowenoid and 6 (2.8%) were papillary. Patients of pagetoid intraepithelial spread showed significantly longer diagnostic delay (p=0.001) and more initial misdiagnoses of blepharitis (p=0.035). After a median follow-up period of 34.0 months, 67 (46%) patients in the non-intraepithelial group, 17 (50%) in the pagetoid group, 8 (30%) in the bowenoid group and 2 (33%) in the papillary group recurred. And 30 (20%) patients in the non-intraepithelial group, 9 (27%) in the pagetoid group and 4 (15%) in the bowenoid group developed metastasis. Moreover, 15 (10%) patients in the non-intraepithelial group, 6 (18%) in the pagetoid group and 1 (3.7%) in the bowenoid group died of SC. Cox regression indicated that pagetoid intraepithelial growth pattern was remarkably associated with increased chances of tumour-related mortality (HR=2.95, 95% CI 1.14 to 7.64, p=0.026). CONCLUSIONS: Intraepithelial tumour invasion was presented in nearly one third of patients with eyelid SC. Pagetoid intraepithelial neoplasia, the predominant growth pattern, significantly increased the risk of tumour-related mortality. Meticulous histopathological intraepithelial examination is recommended for every patient of eyelid SC. Special attention should be paid to those with pagetoid invasion, who may require more intensive managements.
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Adenocarcinoma Sebáceo , Carcinoma in Situ , Carcinoma , Neoplasias de los Párpados , Neoplasias de las Glándulas Sebáceas , Neoplasias Cutáneas , Humanos , Estudios Retrospectivos , Diagnóstico Tardío , Neoplasias Cutáneas/patología , Neoplasias de los Párpados/diagnóstico , Párpados/patología , Neoplasias de las Glándulas Sebáceas/diagnóstico , Adenocarcinoma Sebáceo/patologíaRESUMEN
Extrachromosomal circular DNA (eccDNA), ranging in size from tens to millions of base pairs, is independent of conventional chromosomes. Recently, eccDNAs have been considered an unanticipated major source of somatic rearrangements, contributing to genomic remodeling through chimeric circularization and reintegration of circular DNA into the linear genome. In addition, the origin of eccDNA is considered to be associated with essential chromatin-related events, including the formation of super-enhancers and DNA repair machineries. Moreover, our understanding of the properties and functions of eccDNA has continuously and greatly expanded. Emerging investigations demonstrate that eccDNAs serve as multifunctional molecules in various organisms during diversified biological processes, such as epigenetic remodeling, telomere trimming, and the regulation of canonical signaling pathways. Importantly, its special distribution potentiates eccDNA as a measurable biomarker in many diseases, especially cancers. The loss of eccDNA homeostasis facilitates tumor initiation, malignant progression, and heterogeneous evolution in many cancers. An in-depth understanding of eccDNA provides novel insights for precision cancer treatment. In this review, we summarized the discovery history of eccDNA, discussed the biogenesis, characteristics, and functions of eccDNA. Moreover, we emphasized the role of eccDNA during tumor pathogenesis and malignant evolution. Therapeutically, we summarized potential clinical applications that target aberrant eccDNA in multiple diseases.