Huihui Gu

Lung cancer persists as a major contributor to global cancer-related mortality, with metastasis, recurrence, and therapy resistance posing substantial barriers to effective disease management. CDYL has gained recognition as an epigenetic co-repressor involved in multiple dimensions of oncogenesis. However, its precise mechanistic contributions to non-small cell lung cancer (NSCLC) pathogenesis remain inadequately characterized. In this study, we observed pronounced CDYL overexpression in clinical NSCLC specimens, which exhibited a strong association with advanced disease staging and diminished patient survival. Functional profiling established that CDYL augments proliferative and migratory properties of NSCLC cells in vitro, whereas its genetic suppression markedly impaired tumor development in murine xenograft models. Mechanistically, we uncovered the deubiquitinating enzyme OTUB1 as a critical upstream effector that interacts with and stabilizes CDYL, thereby elevating its protein abundance. Further exploration demonstrated that CDYL confers cellular resistance to cuproptosis, a recently delineated copper-induced modality of regulated cell death. Through integrated transcriptomic and epigenomic interrogation, we elucidated that CDYL collaborates with EZH2 to promote H3K27me3 enrichment at the promoter region of the transcription factor SOX18, resulting in its transcriptional repression. Subsequent investigations revealed that SOX18 transcriptionally activates FDX1, a central regulator of cuproptosis. Consequently, CDYL-driven SOX18 repression leads to attenuated FDX1 expression, suppression of cuproptosis, and accelerated tumor progression. Importantly, administration of the copper chelator tetrathiomolybdate (TTM) counteracted the tumor-restraining consequences of CDYL ablation in vivo. Collectively, our findings unveil the OTUB1/CDYL/SOX18/FDX1 signaling cascade as a previously uncharacterized regulatory circuit that facilitates lung cancer progression through cuproptosis inhibition, providing new insights into the epigenetic regulation of cuproptosis and identifying potential therapeutic targets for NSCLC. Proposed molecular mechanism: OTUB1-mediated deubiquitination stabilizes CDYL, which recruits EZH2 to deposit H3K27me3 at the SOX18 promoter, thereby repressing SOX18 expression and subsequent FDX1 transactivation, leading to cuproptosis suppression and lung cancer progression.

Apomixis is a reproductive process that produces clonal seeds while bypassing meiosis (or apomeiosis) without undergoing fertilization (or pseudo-fertilization). The progenies are genetically cloned from their parents, retaining the parental genotype, and have great potential for the preservation of genes of interest and the fixing of heterosis. The hallmark components of apomixis include the formation of female gametes without meiosis, the development of fertilization-independent embryos, and the formation of functional endosperm. Understanding and utilizing the molecular mechanism of apomixis has far-reaching implications for plant genetic breeding and agricultural development. Therefore, this study focuses on the classification, influencing factors, genetic regulation, and molecular mechanism of apomixis, as well as progress in the research and application of apomixis-related genes in plant breeding. This work will elucidate the molecular mechanisms of apomixis and its application for plant genetic improvement.

NOP2, a member of the NOL1/NOP2/SUN domain (NSUN) family, is responsible for catalyzing the posttranscriptional modification of RNA through 5-methylcytosine (m5C). Dysregulation of m5C modification has been linked to the pathogenesis of various malignant tumors. Herein, we investigated the expression of NOP2 in lung adenocarcinoma (LUAD) tissues and cells, and found that it was significantly upregulated. Moreover, lentivirus-mediated overexpression of NOP2 in vitro resulted in enhanced migration and invasion capabilities of lung cancer cells, while in vivo experiments demonstrated its ability to promote the growth and metastasis of xenograft tumors. In contrast, knockdown of NOP2 effectively inhibited the growth and metastasis of lung cancer cells. RNA-sequencing was conducted to ascertain the downstream targets of NOP2, and the findings revealed a significant upregulation in EZH2 mRNA expression upon overexpression of NOP2. Subsequent validation experiments demonstrated that NOP2 exerted an m5C-dependent influence on the stability of EZH2 mRNA. Additionally, our investigations revealed a co-regulatory relationship between NOP2 and the m5C reader protein ALYREF in modulating the stability of EZH2 mRNA. Notably, the NOP2/EZH2 axis facilitated the malignant phenotype of lung cancer cells by inducing epithelial–mesenchymal transition (EMT) both in vitro and in vivo. Mechanistically, ChIP analysis proved that EZH2 counteracted the impact of NOP2 on the occupancy capacity of EZH2 and H3K27me3 in the promoter regions of E-cadherin, a gene crucial for regulating EMT. In a word, our research highlights the significant role of NOP2 in LUAD and offers novel mechanistic insights into the NOP2/ALYREF/EZH2 axis, which holds promise as a potential target for lung cancer therapy.

RNA methylation is widespread in nature. Abnormal expression of proteins associated with RNA methylation is strongly associated with a number of human diseases including cancer. Increasing evidence suggests that targeting RNA methylation holds promise for cancer treatment. This review specifically describes several common RNA modifications, such as the relatively well‐studied N6‐methyladenosine, as well as 5‐methylcytosine and pseudouridine (Ψ). The regulatory factors involved in these modifications and their roles in RNA are also comprehensively discussed. We summarise the diverse regulatory functions of these modifications across different types of RNAs. Furthermore, we elucidate the structural characteristics of these modifications along with the development of specific inhibitors targeting them. Additionally, recent advancements in small molecule inhibitors targeting RNA modifications are presented to underscore their immense potential and clinical significance in enhancing therapeutic efficacy against cancer.Key Points: In this paper, several important types of RNA modifications and their related regulatory factors are systematically summarised. Several regulatory factors related to RNA modification types were associated with cancer progression, and their relationships with cancer cell migration, invasion, drug resistance and immune environment were summarised. In this paper, the inhibitors targeting different regulators that have been proposed in recent studies are summarised in detail, which is of great significance for the development of RNA modification regulators and cancer treatment in the future.

Background: WRINKLED1 (WRI1) encodes a transcription factor, belonging to the APETALA2 (AP2) family, and plays a key role in regulating plant oil biosynthesis. As a newly woody oil crop, tree peony (Paeonia rockii) was notable for the abundant unsaturated fatty acids in its seed oil. However, the role of WRI1 during the accumulation of P. rockii seeds oil remains largely unknown. Results: In this study, a new member of the WRI1 family was isolated from P. rockii and was named PrWRI1. The ORF of PrWRI1 consisted of 1269 nucleotides, encoding a putative protein of 422 amino acids, and was highly expressed in immature seeds. Subcellular localization analysis in onion inner epidermal cells showed that PrWRI1 was located at the nucleolus. Ectopic overexpression of PrWRI1 could significantly increase the total fatty acid content in Nicotiana benthamiana leaf tissue and even PUFAs in transgenic Arabidopsis thaliana seeds. Furthermore, the transcript levels of most genes related to fatty acids (FA) synthesis and triacylglycerol (TAG) assembly were also up-regulated in transgenic Arabidopsis seeds. Conclusions: Together, PrWRI1 could push carbon flow to FA biosynthesis and further enhance the TAG amount in seeds with a high proportion of PUFAs.

Drought can seriously hinder the growth of plants, resulting in reduced crop yield and quality. At present, the tolerance of DEAD-box helicases (DHC) to abiotic stresses, such as drought, high salinity, low temperature, and high temperature, has been confirmed in a variety of plants; therefore, using DEAD-box helicases to develop stress-resistant plants has great application prospects. In this study, Brassica rapa was used as a model to explore the response of the BrDHC1 gene to drought stress by creating RNA interference and overexpressing lines in B. rapa. The mechanism of BrDHC1 involved in drought resistance was revealed by the analysis of morphological characteristics, physiological indicators, and expression analysis of related stress response genes. The results showed that the overexpression of the BrDHC1 gene was more conducive to enhancing the resilience of plants under drought stress in B. rapa. Taken together, these results confirmed BrDHC1 as a newly identified DEAD-box helicase gene that could actively regulate plant growth and development under drought stress in B. rapa.

Newly synthetic autotetraploid rice shows lower pollen fertility and seed setting rate relative to diploid rice, which hinders its domestication and breeding. In this study, cytological analysis showed that at meiosis I stage, an unbalanced segregation of homologous chromosomes, occurred as well as an early degeneration of tapetal cells in autotetraploid rice. We identified 941 differentially expressed proteins (DEPs) in anthers (meiosis I), including 489 upregulated and 452 downregulated proteins. The DEPs identified were related to post-translational modifications such as protein ubiquitination. These modifications are related to chromatin remodeling and homologous recombination abnormalities during meiosis. In addition, proteins related to the pentose phosphate pathway (BGIOSGA016558, BGIOSGA022166, and BGIOSGA028743) were downregulated. This may be related to the failure of autotetraploid rice to provide the energy needed for cell development after polyploidization, which then ultimately leads to the early degradation of the tapetum. Moreover, we also found that proteins (BGIOSGA017346 and BGIOSGA027368) related to glutenin degradation were upregulated, indicating that a large loss of glutenin cannot provide nutrition for the development of tapetum, resulting in early degradation of tapetum. Taken together, these evidences may help to understand the differences in anther development between diploid and autotetraploid rice during meiosis.

PARP proteins are highly conserved homologs among the eukaryotic poly (ADP-ribose) polymerases. After activation, ADP-ribose polymers are synthesized on a series of ribozymes that use NAD+ as a substrate. PARPs participate in the regulation of various important biological processes, such as plant growth, development, and stress response. In this study, we characterized the homologue of PARP1 in B. rapa using RNA interference (RNAi) to reveal the underlying mechanism responding to drought stress. Bioinformatics and expression pattern analyses demonstrated that two copy numbers of PARP1 genes (BrPARP1.A03 and BrPARP1.A05) in B. rapa following a whole-genome triplication (WGT) event were retained compared with Arabidopsis, but only BrPARP1.A03 was predominantly transcribed in plant roots. Silencing of BrPARP1 could markedly promote root growth and development, probably via regulating cell division, and the transgenic Brassica lines showed more tolerance under drought treatment, accompanied with substantial alterations including accumulated proline contents, significantly reduced malondialdehyde, and increased antioxidative enzyme activity. In addition, the findings showed that the expression of stress-responsive genes, as well as reactive oxygen species (ROS)-scavenging related genes, was largely reinforced in the transgenic lines under drought stress. In general, these results indicated that BrPARP1 likely responds to drought stress by regulating root growth and the expression of stress-related genes to cope with adverse conditions in B. rapa.

Color is an essential agronomic trait and the consumption of high anthocyanin containing vegetables in daily diet does provide benefits to human health, but the mechanisms on anthocyanin accumulation in tender pods of okra (Abelmoschus esculentus L.) were totally unknown. In this study, a wide characterization and quantitation of anthocyanins and flavonols in tender pods of 15 okra varieties were performed by UHPLC-Q-Orbitrap HRMS for the first time. Two major anthocyanins (delphinidin 3-O-sambubioside and cyanidin 3-O-sambubioside) and six kinds of flavonol glycosides (most are quercetin-based) were identified and quantified. The coloration of the purple okra pod mainly arises from the accumulation of both delphinidin 3-O-sambubioside and cyanidin 3-O-sambubioside in most of purple varieties (Hong Yu, Bowling Red and Burgundy), except Jing Orange. The significant differences in the compositions and contents of anthocyanins are responsible for the pod color ranging from brick-red to purplish-red among the various okra cultivars. Furthermore, four representative okra cultivars exhibiting obvious differences in anthocyanin accumulation were further analyzed with transcriptome and more than 4000 conserved differentially expressed genes were identified across the three compared groups (B vs. BR, B vs. HY and B vs. JO). Based on the comprehensive analysis of transcriptomic data, it was indicated that MBW complex consisting of AeMYB114, AeTT8, and AeTTG1 and other transcriptional factors coordinately regulate the accumulation of anthocyanins via the transcriptional regulation of structural genes. Moreover, four independent working models explaining the diversities of anthocyanin pigmentation in okra pods were also proposed. Altogether, these results improved our understanding on anthocyanin accumulation in okra pods, and provided strong supports for the development of okra pod as a functional food in the future.