PD-L1 deglycosylation promotes its nuclear translocation and accelerates DNA double-strand-break repair in cancer.

Resistance to radiotherapy is a major barrier during cancer treatment. Here using genome-scale CRISPR/Cas9 screening, we identify CD274 gene, which encodes PD-L1, to confer lung cancer cell resistance to ionizing radiation (IR). Depletion of endogenous PD-L1 delays the repair of IR-induced DNA double-strand breaks (DSBs) and PD-L1 loss downregulates non-homologous end joining (NHEJ) while overexpression of PD-L1 upregulates NHEJ.

DNA-PK is activated by SIRT2 deacetylation to promote DNA double-strand break repair by non-homologous end joining.

DNA-dependent protein kinase (DNA-PK) plays a critical role in non-homologous end joining (NHEJ), the predominant pathway that repairs DNA double-strand breaks (DSB) in response to ionizing radiation (IR) to govern genome integrity. The interaction of the catalytic subunit of DNA-PK (DNA-PKcs) with the Ku70/Ku80 heterodimer on DSBs leads to DNA-PK activation; however, it is not known if upstream signaling events govern this activation. Here, we reveal a regulatory step governing DNA-PK activation by SIRT2 deacetylation, which facilitates DNA-PKcs localization to DSBs and interaction with Ku, thereby promoting DSB repair by NHEJ.

Resilient Consensus Control for Multi-Agent Systems: A Comparative Survey.

Due to the openness of communication network and the complexity of system structures, multi-agent systems are vulnerable to malicious network attacks, which can cause intense instability to these systems. This article provides a survey of state-of-the-art results of network attacks on multi-agent systems. Recent advances on three types of attacks, i.

SAMHD1 deacetylation by SIRT1 promotes DNA end resection by facilitating DNA binding at double-strand breaks.

Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) has a dNTPase-independent function in promoting DNA end resection to facilitate DNA double-strand break (DSB) repair by homologous recombination (HR); however, it is not known if upstream signaling events govern this activity. Here, we show that SAMHD1 is deacetylated by the SIRT1 sirtuin deacetylase, facilitating its binding with ssDNA at DSBs, to promote DNA end resection and HR. SIRT1 complexes with and deacetylates SAMHD1 at conserved lysine 354 (K354) specifically in response to DSBs.

Metabolomic Comparison of Patients With Colorectal Cancer at Different Anticancer Treatment Stages.

Background: The difficulties of early diagnosis of colorectal cancer (CRC) result in a high mortality rate. The ability to predict the response of a patient to surgical resection or chemotherapy may be of great value for clinicians when planning CRC treatments. Metabolomics is an emerging tool for biomarker discovery in cancer research.

Overcoming acquired resistance to third-generation EGFR inhibitors by targeting activation of intrinsic apoptotic pathway through Mcl-1 inhibition, Bax activation, or both.

Treatment of EGFR-mutant non-small cell lung cancer (NSCLC) with mutation-selective third-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib has achieved remarkable success in the clinic. However, the immediate challenge is the emergence of acquired resistance, limiting the long-term remission of patients. This study suggests a novel strategy to overcome acquired resistance to osimertinib and other third-generation EGFR-TKIs through directly targeting the intrinsic apoptotic pathway.

Discovery of Small Molecule Bak Activator for Lung Cancer Therapy.

Bak is a major proapoptotic Bcl2 family member and a required molecule for apoptotic cell death. High levels of endogenous Bak were observed in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cell lines. Increased Bak expression was correlated with poor prognosis of NSCLC patients, suggesting that Bak protein is an attractive target for lung cancer therapy.

Epigenetic modulation of FBW7/Mcl-1 pathway for lung cancer therapy.

Methylation induces epigenetic silencing of tumor suppressor genes in human lung cancer. Inhibition of DNA methyltransferases by decitabine (DAC) can demethylate and activate epigenetically silenced tumor suppressor genes. Epigenetic therapy using DAC should be an attractive strategy for lung cancer therapy.

TGF-β causes Docetaxel resistance in Prostate Cancer via the induction of Bcl-2 by acetylated KLF5 and Protein Stabilization.

Prostate cancer is the second leading cause of cancer-related death in the United States. As a first line treatment for hormone-refractory prostate cancer, docetaxel (DTX) treatment leads to suboptimal effect since almost all patients eventually develop DTX resistance. In this study, we investigated whether and how TGF-β affects DTX resistance of prostate cancer.

EZH2 has a non-catalytic and PRC2-independent role in stabilizing DDB2 to promote nucleotide excision repair.

Small cell lung cancer (SCLC) is a highly aggressive malignancy with poor outcomes associated with resistance to cisplatin-based chemotherapy. Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 (PRC2), which silences transcription through trimethylation of histone H3 lysine 27 (H3K27me3) and has emerged as an important therapeutic target with inhibitors targeting its methyltransferase activity under clinical investigation. Here, we show that EZH2 has a non-catalytic and PRC2-independent role in stabilizing DDB2 to promote nucleotide excision repair (NER) and govern cisplatin resistance in SCLC.

Correction to: Small Molecule KRAS Agonist for Mutant KRAS Cancer Therapy.

An amendment to this paper has been published and can be accessed via the original article.

Bcl2-induced DNA replication stress promotes lung carcinogenesis in response to space radiation.

Space radiation is characterized by high-linear energy transfer (LET) ionizing radiation. The relationships between the early biological effects of space radiation and the probability of cancer in humans are poorly understood. Bcl2 not only functions as a potent antiapoptotic molecule but also as an oncogenic protein that induces DNA replication stress.

Mcl-1 Interacts with Akt to Promote Lung Cancer Progression.

Mcl-1 is a unique antiapoptotic Bcl2 family protein that functions as a gatekeeper in manipulating apoptosis and survival in cancer cells. Akt is an oncogenic kinase that regulates multiple cellular functions and its activity is significantly elevated in human cancers. Here we discovered a cross-talk between Mcl-1 and Akt in promoting lung cancer cell growth.

Prognostic significance of periostin in colorectal cancer.

Accumulating evidence suggests that periostin is frequently upregulated in tissue injury, inflammation, fibrosis and tumor progression. Periostin expression in cancer cells can promote metastatic potential of colorectal cancer (CRC) via activating PI3K/Akt signaling pathway. Moreover, periostin is observed mainly in tumor stroma and cytoplasm of cancer cells, which may facilitate aggressiveness of CRC.

Acetylation regulates ribonucleotide reductase activity and cancer cell growth.

Ribonucleotide reductase (RNR) catalyzes the de novo synthesis of deoxyribonucleoside diphosphates (dNDPs) to provide dNTP precursors for DNA synthesis. Here, we report that acetylation and deacetylation of the RRM2 subunit of RNR acts as a molecular switch that impacts RNR activity, dNTP synthesis, and DNA replication fork progression. Acetylation of RRM2 at K95 abrogates RNR activity by disrupting its homodimer assembly.

Small Molecule KRAS Agonist for Mutant KRAS Cancer Therapy.

Background: Lung cancer patients with KRAS mutation(s) have a poor prognosis due in part to the development of resistance to currently available therapeutic interventions. Development of a new class of anticancer agents that directly targets KRAS may provide a more attractive option for the treatment of KRAS-mutant lung cancer.

Results: Here we identified a small molecule KRAS agonist, KRA-533, that binds the GTP/GDP-binding pocket of KRAS.

Tumor pyruvate kinase M2: A promising molecular target of gastrointestinal cancer.

Gastrointestinal (GI) cancer is one of the most common causes of cancer-related deaths worldwide. Tumor markers are valuable in detecting post-surgical recurrence or in monitoring response to chemotherapy. Pyruvate kinase isoform M2 (PKM2), a glycolytic enzyme catalyzing conversion of phosphoenolpyruvate (PEP) to pyruvate, confers a growth advantage to the tumor cells and enables them to adapt to the tumor microenvironment.

Cell Synchronization by Double Thymidine Block.

Cell synchronization is widely used in studying mechanisms involves in regulation of cell cycle progression. Through synchronization, cells at distinct cell cycle stage could be obtained. Thymidine is a DNA synthesis inhibitor that can arrest cell at G1/S boundary, prior to DNA replication.

Comparison of Microbiota in Patients Treated by Surgery or Chemotherapy by 16S rRNA Sequencing Reveals Potential Biomarkers for Colorectal Cancer Therapy.

Colorectal cancer (CRC) is the third most diagnosed cancer worldwide due to its high difficulty in early diagnosis, high mortality rate and short life span. Recent publications have demonstrated the involvement of the commensal gut microbiota in the initiation, progression and chemoresistance of CRC. However, this microbial community has not been explored within CRC patients after anti-cancer treatments.