In this review, we summarize the multiple functions of NQO1, its established roles in redox processes and potential roles in redox control that are currently emerging. NQO1 has attracted interest due to its roles in cell defense and marked inducibility during cellular stress. Exogenous substrates for NQO1 include many xenobiotic quinones. Since NQO1 is highly expressed in many solid tumors, including via upregulation of Nrf2, the design of compounds activated by NQO1 and NQO1-targeted drug delivery have been active areas of research. Endogenous substrates have also been proposed and of relevance to redox stress are ubiquinone and vitamin E quinone, components of the plasma membrane redox system. Established roles for NQO1 include a superoxide reductase activity, NAD+ generation, interaction with proteins and their stabilization against proteasomal degradation, binding and regulation of mRNA translation and binding to microtubules including the mitotic spindles. We also summarize potential roles for NQO1 in regulation of glucose and insulin metabolism with relevance to diabetes and the metabolic syndrome, in Alzheimer's disease and in aging. The conformation and molecular interactions of NQO1 can be modulated by changes in the pyridine nucleotide redox balance suggesting that NQO1 may function as a redox-dependent molecular switch.

The diverse functionality of NQO1 and its roles in redox control

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. In the past decade, there have been improvements in non-drug therapies and drug therapies for HCC treatment. Non-drug therapies include hepatic resection, liver transplantation, transarterial chemoembolization (TACE) and ablation. The former two surgical treatments are beneficial for patients with early and mid-stage HCC. As the first choice for non-surgical treatment, different TACE methods has been developed and widely used in combination therapy. Ablation has become an important alternative therapy for the treatment of small HCC or cases of unresectable surgery. Meanwhile, the drugs including small molecule targeted drugs like sorafenib and lenvatinib, monoclonal antibodies such as nivolumab are mainly used for the systematic treatment of advanced HCC. Besides strategies described above are recommended as first-line therapies due to their significant increase in mean overall survival, there are also potential drugs in clinical trials or under preclinical development. In addition, a number of potential preclinical surgical or adjuvant therapies are being studied, such as oncolytic virus, mesenchymal stem cells, biological clock, gut microbiome composition and peptide vaccine, all of which have shown different degrees of inhibition on HCC. With some potential anti-HCC drugs being reported, many promising therapeutic targets in related taxonomic signaling pathways including cell cycle, epigenetics, tyrosine kinase and so on that affect the progression of HCC have also been found. Together, the rational application of existing therapies and drugs as well as the new strategies will bring a bright future for the global cure of HCC in the coming decades.

Recent progress in treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) ranks fourth in cancer-related mortality worldwide. N1-methyladenosine (m1A), a methylation modification on RNA, is gaining attention for its role across diverse biological processes. However, m1A-related regulatory genes expression, its relationship with clinical prognosis, and its role in HCC remain unclear. In this study, we utilized The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) database to investigate alterations within 10 m1A-related regulatory genes and observed a high mutation frequency (23/363). Cox regression analysis and least absolute shrinkage and selection operator were used to explore the association between m1A-related regulatory genes expression and HCC patient survival and identified four regulators that were remarkably associated with HCC patient prognosis. Additionally, an independent cohort from International Cancer Genome Consortium was studied to validate our discoveries and found to be consistent with those in the TCGA dataset. In terms of mechanism, gene set enrichment analysis linked these four genes with various physiological roles in cell division, the MYC pathway, protein metabolism, and mitosis. Kyoto Encyclopedia of Genes and Genomes analysis revealed that PI3K/Akt signaling pathway had potential relevance to m1A-related regulatory genes in HCC. These findings indicate that m1A-related regulatory genes may play crucial roles in regulating HCC progression and be exploited for diagnostic and prognostic purposes.

/pdf/gene-signatures-and-prognostic-values-of-m1a-related-1mhi5y9b84.pdf

Gene signatures and prognostic values of m1A-related regulatory genes in hepatocellular carcinoma.

Sirtuin 6 (SIRT6) is a NAD+-dependent nuclear deacylase and mono-ADP-ribosylase with a wide spectrum of substrates. Through its pleiotropic activities, SIRT6 modulates either directly or indirectly key processes linked to cell fate determination and oncogenesis such as DNA damage repair, metabolic homeostasis, and apoptosis. SIRT6 regulates the expression and activity of both pro-apoptotic (e.g., Bax) and anti-apoptotic factors (e.g., Bcl-2, survivin) in a context-depending manner. Mounting evidence points towards a double-faced involvement of SIRT6 in tumor onset and progression since the block or induction of apoptosis lead to opposite outcomes in cancer. Here, we discuss the features and roles of SIRT6 in the regulation of cell death and cancer, also focusing on recently discovered small molecule modulators that can be used as chemical probes to shed further light on SIRT6 cancer biology and proposed as potential new generation anticancer therapeutics.

The Two-Faced Role of SIRT6 in Cancer

SIRT6 transcriptionally regulates fatty acid transport by suppressing PPARγ.

Our previous study has demonstrated that NAD(P)H: quinone oxidoreductase 1 (NQO1) is significantly upregulated in human liver cancer where it potentiates the apoptosis evasion of liver cancer cell. However, the underlying mechanisms of the oncogenic function of NQO1 in HCC have not been fully elucidated. Expression of NQO1, SIRT6, AKT and X-linked inhibitor of apoptosis protein (XIAP) protein were measured by western blotting and immunohistochemistry. Additionally, the interaction between NQO1 and potential proteins were determined by immunoprecipitation assays. Furthermore, the effect of NQO1 and SIRT6 on tumor growth was determined in cell model and orthotopic tumor implantation model. We found that NQO1 overexpression in HCC enhanced SIRT6 protein stability via inhibiting ubiquitin-mediated 26S proteasome degradation. High level of SIRT6 reduced acetylation of AKT which resulted in increased phosphorylation and activity of AKT. Activated AKT subsequently phosphorylated anti-apoptotic protein XIAP at Ser87 which determined its protein stability. Reintroduction of SIRT6 or AKT efficiently rescued NQO1 knock-out-mediated inhibition of growth and induction of apoptosis. In orthotopic mouse model, NQO1 knock-out inhibited tumor growth and induced apoptosis while this effect was effectively rescued by SIRT6 overexpression or MG132 treatment partially. Collectively, these results reveal an oncogenic function of NQO1 in sustaining HCC cell proliferation through SIRT6/AKT/XIAP signaling pathway.

/pdf/nqo1-potentiates-apoptosis-evasion-and-upregulates-xiap-via-5g9x9jon53.pdf

NQO1 potentiates apoptosis evasion and upregulates XIAP via inhibiting proteasome-mediated degradation SIRT6 in hepatocellular carcinoma

Hepatitis B virus (HBV) infection remains a global public health problem. Nearly 257 million people worldwide have been infected with HBV, resulting in 887,000 people dying of cirrhosis or liver cancer caused by chronic hepatitis B (CHB) annually. Therefore, identification of new targets against HBV is urgently needed. Long noncoding RNAs (LncRNAs) have gained widespread attention in recent years due to their function in cancer, inflammation and other diseases. Notably, a growing number of lncRNAs have been found to play a role in HBV development. In the present study, we first identified a famous lncRNA, HOTAIR, which was significantly up-regulated in HBV-infected cells and PBMCs from CHB patients. Furthermore, we evaluated the clinical relevance of HOTAIR in 20 CHB patients and found that higher levels of HOTAIR expression were associated with higher ALT/AST levels and were positively correlated with HBsAg and HBV DNA levels. In addition, functional analysis showed that HOTAIR promoted HBV transcription and replication by elevating the activities of HBV promoters via modulation of the levels of cccDNA-bound SP1. In conclusion, our study reveals that HOTAIR expression is correlated with the clinicopathological and physiological characteristics of HBV. Thus, HOTAIR may serve as a novel HBV diagnostic and therapeutic biomarker based on its ability to facilitate HBV transcription and replication.

Yi-Ping Qin

Papers

NQO1 potentiates apoptosis evasion and upregulates XIAP via inhibiting proteasome-mediated degradation SIRT6 in hepatocellular carcinoma

LncRNA HOTAIR modulates hepatitis B virus transcription and replication by enhancing SP1 transcription factor