Post-translational modifications (PTMs) play a pivotal role in epigenetic regulation and are key pathways for modulating protein functionality. PTMs involve the covalent attachment of distinct chemical groups, such as succinyl, crotonyl, and lactyl, at specific protein sites, which alter protein structure, function, stability, and activity, ultimately influencing biological processes. Recently, metabolically derived short-chain acylation modifications (with acyl groups containing fewer than six carbon atoms) have been progressively identified, such as butyrylation, succinylation, crotonylation, and lactylation, differing from traditional acetylation in structure, physicochemical properties, function, and regulation. Aberrant short-chain acyl-PTMs are often associated with tumorigenesis. Research highlights that PTMs like succinylation and lactylation are essential in regulating tumor metabolism, drug resistance, and immune responses. This review elucidates the regulatory mechanisms of eight short-chain acyl-PTMs—butyrylation, succinylation, crotonylation, malonylation, glutarylation, 2-hydroxyisobutyrylation, β-hydroxybutyrylation, and lactylation—that are involved in tumor initiation and progression. Their roles in controlling tumor genomic stability, gene transcription, protein stability, enzyme activity, and nuclear localization are summarized, demonstrating their impact on related biological processes such as tumor metabolism, multi-drug resistance, and immune evasion. Additionally, the review provides an overview of current drug research targeting enzymes that regulate PTMs, offering critical insights to advance therapeutic strategies for cancer treatment.
Background: The epidemiological profiles of gastrointestinal (GI) cancers vary across countries and over time, largely reflecting variations in risk factors and screening practices. We aimed to provide an overview of the current global burden of the five major types of GI cancers and conduct an updated evaluation of the long-term trends of GI cancers.
Methods: The updated numbers of new cases and deaths, and age-standardized rates (ASR), of the five GI cancers for 185 countries were sourced from the GLOBOCAN 2022, and presented by cancer site, continent, and human development index (HDI). For 43 countries, annual incidence and mortality data were obtained from the Cancer Incidence in Five Continents Plus and World Health Organization mortality databases, supplemented by the mortality data from the Disease Surveillance Points system for China. We compared the long-term trends of ASRs across countries since 1980, and estimated average annual percent changes (AAPCs) for the recent period 2003-2017.
Results: In 2022, there were 4,783,391 new cases and 3,235,719 deaths from the five GI cancers, accounting for 23.9% and 33.2% of all new cancer cases and deaths worldwide, respectively. Cancers of oesophagus, stomach, and liver were more common in Asian and high HDI countries, and colorectal and pancreatic cancer in western and very high HDI countries. Downward trends were observed in almost all countries for gastric cancer and most countries for oesophageal cancer. For colorectal cancer, the most favorable and unfavorable trends were found in 10 and 19 countries respectively. The largest decreases in liver cancer burden were mainly in eastern and southeastern Asia, while increases were seen in North America, Oceania, and Northern Europe, with AAPCs of 3%∼7% for incidence and 2%∼9% for mortality during 2003-2017. Half of the included countries showed increases in pancreatic cancer burden, with the largest AAPCs in Cyprus, Thailand, India,Türkiye, France, and Belarus for incidence, and Türkiye, Thailand, and China for mortality.
Conclusions: Deviating patterns were found for GI cancers worldwide. Multi-setting studies might provide insights into the underlying etiologies of these cancers, and identify areas where urgent cancer control strategies are needed.
Background: Radiotherapy (RT) is a key treatment modality in cancer therapy, utilizing high-energy radiation to directly kill tumor cells. Recent research has increasingly highlighted RT's potential to indirectly enhance antitumor immunity. However, this immune activation alone often fails to generate sustained systemic antitumor responses. In this study, we aimed to investigate the antitumor effects of combining cholesterolized toll-like receptor 7 (TLR7) agonist liposomes, specifically 1V209-Cho-Lip, with RT.
Methods: Mouse tumor models were used to assess the impact of combining 1V209-Cho-Lip with RT on tumor progression and modification of the tumor microenvironment. In vitro, primary mouse bone marrow-derived dendritic cells (BMDCs) were utilized to investigate changes in function and the activated pathways through RNA sequencing. Additionally, we explored the role of oxidized mitochondrial DNA (ox-mtDNA) released from irradiated tumor cells as a damage-associated molecular pattern in modulating immune responses. The involvement of interleukin-1β (IL-1β) and the inflammasome pathway in the antitumor efficacy of the combined treatment was evaluated using Il-1β-/- and cysteinyl aspartate specific proteinase 1 knockout (Casp1-/-) mouse models.
Results: The combination of 1V209-Cho-Lip and RT significantly inhibited tumor growth and induced antitumor immunity in tumor models. This combination therapy enhanced maturation, antigen presentation and IL-1β secretion of dendritic cells (DCs) in vitro. Ox-mtDNA released from irradiated tumor cells synergized with 1V209-Cho-Lip to activate the inflammasome pathway in DCs. The antitumor effect of the combined therapy was significantly reduced in Il-1β-/- and Casp1-/- mice.
Conclusions: This study suggests that the combination of 1V209-Cho-Lip with RT might be a promising antitumor strategy and further studies are warranted to explore the clinical relevance of this combination therapy.
Background: Hepatocellular carcinoma (HCC) is a deadly malignancy known for its ability to evade immune surveillance. NOP2/Sun RNA methyltransferase family member 2 (NSUN2), an RNA methyltransferase involved in carcinogenesis, has been associated with immune evasion and energy metabolism reprogramming. This study aimed to examine the molecular mechanisms underlying the involvement of NSUN2 in immune evasion and metabolic reprogramming of HCC.
Methods: Single-cell transcriptomic sequencing was applied to examine cellular composition changes, particularly immune cell dynamics, in HCC and adjacent normal tissues. Bulk RNA-seq and proteomics identified key genes and proteins. Methylation sequencing and methylated RNA immunoprecipitation (MeRIP) were carried out to characterize the role of NSUN2 in 5-methylcytosine (m5C) modification of sterol O-acyltransferase 2 (SOAT2). Clinical samples from 30 HCC patients were analyzed using reverse transcription-quantitative polymerase chain reaction and Western blotting. Gene expression was manipulated using CRISPR/Cas9 and lentiviral vectors. In vitro co-culture models and metabolomics were used to study HCC cell-T cell interactions, energy metabolism, and immune evasion. Tumor growth in an orthotopic mouse model was monitored by bioluminescence imaging, with subsequent measurements of tumor weight, volume, and immunohistochemical staining.
Results: Single-cell transcriptomic analysis identified a marked increase in malignant cells in HCC tissues. Cell communication analysis indicated that tumor cells might promote cancer progression by evading immune clearance. Multi-omics analyses identified NSUN2 as a key regulator in HCC development. MeRIP confirmed that NSUN2 facilitated the m5C modification of SOAT2. Analysis of human HCC tissue samples demonstrated pronounced upregulation of NSUN2 and SOAT2, along with elevated m5C levels in HCC tissues. In vitro experiments uncovered that NSUN2 augmented the reprogramming of energy metabolism and repressed the activity and cytotoxicity of CD8+ T cells, contributing to immune evasion. In vivo studies further substantiated the role of NSUN2 in fostering immune evasion and tumor formation of HCC by modulating the m5C modification of SOAT2.
Conclusions: The findings highlight the critical role of NSUN2 in driving HCC progression through the regulation of m5C modification on SOAT2. These findings present potential molecular markers for HCC diagnosis and therapeutic targets for its treatment.
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