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As signal molecules in aerobic organisms, locally accumulated ROS have been reported to balance cell division and differentiation in the root meristem. Protein posttranslational modifications such as lysine acetylation play critical roles in controlling a variety of cellular processes. However, the mechanism by which ROS regulate root development is unknown. In addition, how protein lysine acetylation is regulated and whether cellular ROS levels affect protein lysine acetylation remain unclear.We aimed to elucidate the relationship between ROS and protein acetylation by exploring a rice mutant plant that displays a decreased level of ROS in postembryonic crown root (CR) cells and severe defects in CR development.First, proteomic analysis was used to find candidate proteins responsible for the decrease of ROS detected in the wox11 mutant. Then, biochemical, molecular, and genetic analyses were used to study WOX11-regulated genes involved in ROS homeostasis. Finally, acetylproteomic analysis of wild type and wox11 roots treated with or without potassium iodide (KI) and hydrogen peroxide (HWe demonstrated that WOX11 was required to maintain ROS homeostasis by upregulating peroxidase genes in the crown root meristem. Acetylproteomic analysis revealed that WOX11-dependent hydrogen peroxide (HWOX11-controlled ROS level in CR meristem cells is required for protein lysine acetylation which represents a mechanism of ROS-promoted CR development in rice.

Current studies have shown that the recent rhythm gene Per1 (Period 1) is expressed down-regulated in various malignancies and plays an important role in tumorigenesis and progression. However, the biological function and mechanism of action of Per1 in non-small cell lung cancer (NSCLC) is not clear. In this study, we demonstrated that miR-29a could inhibit the interaction between Per1 and laminin receptor 1 (LAMR1), and the invasion and migration ability of A549 cells after 8Gy X-ray irradiation showed dynamic changes, firstly weakened or enhanced. The inhibition or overexpression of miR-29a, Per1, and LAMR1 was performed to investigate their roles and mechanisms in vitro. We found that miR-29a was able to significantly inhibit the expression of Per1 gene, while the invasion and migration ability of residual A549 cells after radiation showed a dynamic change of diminished and then enhanced. Further study revealed that the reason for this dynamic change might be that miR-29a affected the binding of laminin (LN) to LAMR1 through the interaction of Per1 and LAMR1. In summary, our study demonstrates for the first time that it may be miR-29a that inhibits the interaction between Per1 and LAMR1, which causes a dynamic change in the invasive migration ability of residual A549 cells after radiation by competitively binding to LN, and that Per1 may serve as a valuable biological target for good or bad prognosis of NSCLC.

Background: We aim to investigate the expression of the peptidylprolyl isomerase A (PPIA) gene in lung adenocarcinoma(LUAD),and to investigate the diagnostic, prognostic value and correlation with immune infiltrates of PPIA in LUAD.Methods: Transcriptional expression profiles of PPIA between LUAD tissues and normal tissues were downloaded from the Cancer Genome Atlas (TCGA).The PPIA protein expression was assessed by the Clinical Proteomic Tumor Analysis Consortium (CPTAC) .Receiver operating characteristic(ROC) curve was used to differentiate LUAD from adjacent normal tissues.Kaplan-Meier method was conducted to assess the effect of PPIA on survival.Protein-protein interaction (PPI) networks were constructed by the STRING.Functional enrichment analyses were performed using the“ClusterProfiler”package.The relationship between PPIA mRNA expression and immune infiltrates was determined by tumor immune estimation resource (TIMER) and tumor-immune system interaction database (TISIDB).Results: The expression of PPIA in LUAD tissues was significantly upregulated than those in adjacent normal tissues. High PPIA mRNA expression was associated with lymph node metastases and high TNM stage. The ROC curve analysis showed that PPIA had an AUC value of 0.804(95% CI: 0.764-0.843).Kaplan-Meier survival analysis showed LUAD patients with high-PPIA had a worse prognosis than those with low-PPIA(mOS: 42.2months VS 87.2months,P＜0.001). Correlation analysis indicated PPIA mRNA expression was correlated with immune infiltrates.PPIA expression had correlations with CD4+ T cell (r = -0.29, P = 5.51e-11),macrophage M1 (r = 0.106, P = 1.84e-02), and B cell (r = -0.181, P =5.40e-5).Conclusion: Our research showed that PPIA could be used as a prognostic biomarker.Up-regulation of PPIA expression is significantly related to poor prognosis and immune infiltration of LUAD and may be a potential therapeutic molecular target for LUAD patients.

WUSCHEL-related Homeobox 11 regulates protein translation via lysine acetylation of ribosome protein mediated by ROS in rice root meristem.

Yunfen Li,1– 4,* Zhengting Chen,1,* Ke Cao,1,* Lan Zhang,1,* Yuhui Ma,1 Shuhui Yu,1 Hanyu Jin,1 Xiaoling Liu,1 Wenhui Li1 1Department of Radiotherapy, Third Affiliated Hospital of Kunming Medical, Yunnan Cancer Hospital, Kunming City, Yunnan Province, People’s Republic of China; 2Department of Oncology, Yunnan Boya Hospital, Kunming City, Yunnan Province, People’s Republic of China; 3College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu City, Sichuan Province, People’s Republic of China; 4Department of Medicine, Lizhu Pharmaceutical Group Co., Ltd., Zhuhai City, Guangdong Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenhui LiDepartment of Radiotherapy, Third Affiliated Hospital of Kunming Medical, Yunnan Cancer Hospital, No.519 Kunzhou Road, Kunming City, Yunnan Province, People’s Republic of ChinaEmail wenhuili2014@163.comPurpose: To investigate the role and underlying mechanism of G9a and CCDC8 in lung cancer radioresistance.Methods: Western blotting assays were used for G9a, CCDC8, H3K9me3 expression detection. MTT assays and clone formation assays were used for measuring cell proliferation activities. Flow cytometry assays were used for cell apoptosis detection. The enrichment of H3K9me3 in CCDC8 promoter was measured by chromatin immunoprecipitation assay.Results: G9a and G9a-mediated H3K9me3 are upregulated in radioresistant lung cancer cells (A549/IR cell and XWLC-05/IR cell). Blocking G9a not only promotes radiosensitivity of A549/IR cell and XWLC-05/IR cell but also reduces aggressive behavior of radioresistant A549 cell/IR and XWLC-05/IR cell. In addition, G9a-controlled H3K9me3 is able to binding to the promoter of tumor suppressor gene CCDC8 and suppresses CCDC8 expression. CCDC8 dysregulation is responsible for G9a-mediated radioresistance of A549/IR cell and XWLC-05/IR cell.Conclusion: G9a and H3K9me3 contribute to the lung cancer radioresistance via modulating CCDC8 expression.Keywords: radiotherapy, lung cancer, G9a, H3K9me3, CCDC8

Lysine acetylation (Kac) is well known to occur in histones for chromatin function and epigenetic regulation. In addition to histones, Kac is also detected in a large number of proteins with diverse biological functions. However, Kac function and regulatory mechanism for most proteins are unclear. In this work, we studied mutation effects of rice genes encoding cytoplasm-localized histone deacetylases (HDAC) on protein acetylome and found that the HDAC protein HDA714 was a major deacetylase of the rice non-histone proteins including many ribosomal proteins (r-proteins) and translation factors that were extensively acetylated. HDA714 loss-of-function mutations increased Kac levels but reduced abundance of r-proteins. In vitro and in vivo experiments showed that HDA714 interacted with r-proteins and reduced their Kac. Substitutions of lysine by arginine (depleting Kac) in several r-proteins enhance, while mutations of lysine to glutamine (mimicking Kac) decrease their stability in transient expression system. Ribo-seq analysis revealed that the hda714 mutations resulted in increased ribosome stalling frequency. Collectively, the results uncover Kac as a functional posttranslational modification of r-proteins which is controlled by histone deacetylases, extending the role of Kac in gene expression to protein translational regulation.

Supplemental Material, sj-pdf-1-tct-10.1177_15330338211016369 for Efficacy and Safety of Platinum-Based Chemotherapy as First-Line Therapy for Metastatic Triple-Negative Breast Cancer: A Meta-Analysis of Randomized Controlled Trials by Fei Lu, Yu Hou, Zhengting Chen, Jie Jiang, Xi He, Yaoxiong Xia, Ke Cao, Li Chang and Wenhui Li in Technology in Cancer Research & Treatment

Aim Ionizing radiation (IR) can induce local and systemic antitumour immune responses to some degree and augment immunotherapeutic efficacy. IR may also increase residual tumour cell invasion and elicit immunosuppression in the tumour microenvironment (TME). It remains poorly understand, whether IR leads to immune negative response or invasive capacity increases in lung adenocarcinoma (LAC). Materials and methods RNA interference (RNAi) was used to silence pituitary tumour-transforming gene-1 (PTTG1) and SMAD3 expression in LAC cells. A coculture system of tumour cells and PBMCs was constructed. Cells were exposed to different doses (0, 4 and 8 Gy) of X-ray irradiation. Flow cytometric analysis and Transwell assays were applied. An orthotopic Lewis lung cancer (LLC) mouse tumour model was established. Bioluminescence imaging (BLI) was used. LLC tumours were exposed to a single 15 Gy dose of X-ray irradiation. Key findings PTTG1 knockdown reinforced the inhibitory effect of IR on the invasive ability of A549 cells and enhanced the antitumour T cell immunity induced by IR via the transforming growth factor-β1 (TGF-β1)/SMAD3 pathway. Positive antitumour immune response and immunosuppression were simultaneously triggered by a single 15 Gy dose of local tumour irradiation. PTTG1 knockdown weakened invasive capacity and promoted the immune response balance induced by IR to tilt towards active immunity, which contributed to reduce metastasis and prolonged overall survival (OS) in orthotopic LLC tumour-bearing mouse. Significance Targeted blockade of PTTG1 and the TGF-β1/SMAD3 pathway may ameliorate the immunosuppressive TME and enhance the systemic antitumour immune response induced by a single high-dose IR treatment.

Radiotherapy (RT) is one of most common treatments for cancer. However, overcoming the failure and side effects of RT as well as radioresistance, recurrence and metastasis remains challenging in cancer treatment. Cellular senescence (CS) is permanent arrested state of cell division induced by various factors, including exposure to ionizing radiation (IR). CS induced by IR contributes to tumour cell control and often even causes side effects in normal cells. Improvement of the therapeutic RT ratio is dependent on more cancer cell death and less normal cell damage. In addition, the biological behaviour of tumour cells after IR has also been linked to CS. This review summarizes our understanding of CS in IR, which may be beneficial for providing new insight for improving the therapeutic outcomes of RT.

Background: Triple-negative breast cancer constitutes approximately 12%-17% of all breast cancer cases, and >33% of patients develop distant metastases. Systemic cytotoxic chemotherapy is the primary treatment for patients with metastatic triple-negative breast cancer; however, the role of first-line platinum-based chemotherapy in these patients remains controversial. This meta-analysis evaluated the efficacy and safety of platinum-based first-line chemotherapy for patients with metastatic triple-negative breast cancer. Methods: We systematically searched the PubMed, Embase, Cochrane, and Clinical Trials registry databases up to June 1, 2020 to identify randomized controlled trials that investigated platinum-based vs. first-line platinum-free chemotherapy in patients with metastatic triple-negative breast cancer. We used fixed and random effects models to calculate pooled hazard ratios and odds ratios with 95% confidence intervals for progression-free and overall survival, objective response rates, and grade 3 and 4 adverse events. Results: Four randomized controlled trials ( N = 590 patients) were included. Platinum-based chemotherapy significantly increased the objective response rates from 43.1% to 62.7% (odds ratio 2.34, 95% confidence interval 1.66-3.28, P < 0.001). Three randomized controlled trials ( N = 414 patients) reported survival outcomes. Patients administered platinum-based regimens showed significantly longer progression-free survival (hazard ratio 0.55, 95% confidence interval 0.37-0.82, P = 0.004) and a nonsignificant trend toward improved overall survival (hazard ratio 0.76, 95% confidence interval 0.57-1.00, P = 0.05). Only 2 studies reported the rates of grade 3 and 4 adverse events; grade 3-4 thrombocytopenia was more commonly associated with platinum-based chemotherapy (odds ratio 7.54, 95% confidence interval 1.37-41.60, P = 0.02) and grade 3-4 fatigue with platinum-free chemotherapy (odds ratio 0.23, 95% confidence interval 0.08-0.68, P = 0.008). Conclusions: First-line platinum-based chemotherapy was associated with significantly increased objective response rates, longer progression-free survival, and a nonsignificant trend toward improved overall survival in patients with metastatic triple-negative breast cancer at the high risk of grade 3-4 thrombocytopenia.

Concurrent radiotherapy and chemotherapy is a widely used, comprehensive treatment for rectal cancer. By studying the impact of concurrent chemoradiotherapy on the invasion and migration of colorectal cancer (CRC) cells and researching the associated molecular mechanisms, the present study aimed to provide a novel method to improve the therapeutic effect of this treatment against CRC. Human HCT116 and HT29 CRC cells were simultaneously treated with 4 Gy of 6 MV X-rays and 10 µmol/l 5-fluorouracil to establish a residual cell model. Transwell migration and invasion experiments were used to analyse the invasion and migration of the cells. The expression of long non-coding (lnc)RNAs was detected using a gene chip, and reverse transcription-quantitative polymerase chain reaction analysis was used to determine lncRNA expression levels. Specific small interfering RNAs were transfected into HCT116 residual cells to silence the expression of the identified key genes. The migration and invasion of residual CRC cells were demonstrated to be significantly increased compared with the original cells. Pvt1 oncogene, long-chain non-protein-coding RNA 152 (LINC00152), and MIR22 host gene were selected as potential targets. However, the migration and invasion of residual HCT116 cancer cells were only significantly decreased following silencing of LINC00152 expression. LINC00152 may therefore be a potential biomarker involved in modulation of the biological characteristics of residual CRC cells following chemoradiotherapy.

Preoperative 5-fluorouracil- (5-FU-) based chemoradiotherapy is a standard treatment for locally advanced colorectal cancer (CRC). However, the effect of 5-FU-based chemoradiotherapy on CRC is limited due to the development of chemoradiation resistance (CRR), and the molecular mechanisms underlying this resistance are yet to be investigated. Recently, circular RNAs (circRNAs), which can function as microRNA sponges, were found to be involved in the development of several cancers. In this study, we focused on clarifying the modulation of the expression profiles of circRNAs in CRR. Microarray analysis identified 71 circRNAs differentially expressed in chemoradiation-resistant CRC cells. Among them, 47 were upregulated and 24 were downregulated by more than twofold. Furthermore, expression modulation of five representative circRNAs was validated by quantitative reverse transcription PCR (qRT-PCR). Moreover, these modulated circRNAs were predicted to interact with 355 miRNAs. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the most modulated circRNAs regulate several cancers and cancer-related pathways, and the possible mechanism underlying CRR was discussed. This is the first report revealing the circRNA modulations in 5-FU chemoradiation-resistant CRC cells by microarray. The study provided a useful database for further understanding CRR and presents potential targets to overcome CRR in CRC.