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In multiple studies, at both transcript and protein levels, increased expression of biomarkers Rrm1, Rrm2 as well as Tyms were observed in NSCLC patients and suggested for their implications in cancer therapy (Grossi F et al. 2015, PMID: 26663950, Maus MK et al. 2013, PMID: 23470290). Silencing of Rrm1 and Rrm2 markedly enhanced the tumor-cytotoxicity of the camptothecin (CPT), a topoisomerase I inhibitor, which might be exploited in chemotherapeutic strategies (Zhang YW et al. 2009, PMID: 19416980). In addition, in cellular response to DNA damage, up-regulation of RRM2 transcription in human cells involves an ATR/ATM-Chk1-E2F1 pathway for the cell survival. Accordingly, in PLACs, Rrm1 and Rrm2 genes were identified with TF-binding sites for E2F1 in promoter analysis (see supplementary table of composite module) and transcript expression of E2F1 was slightly increased. This suggests E2F1 transcription factor is involved in regulation of c-Myc responsive Rrm1 and Rrm2 genes in PLACs. Furthermore, expression of RRM1 and RRM2 was reported as a novel prognostic marker in advanced NSCLC receiving chemotherapy (Wang L. et al. 2014, PMID: 24155212).
Other metabolic genes overexpressed in lung cancer
An important finding of the present study was nearly 15-fold strong up-expression of arginase-1 in lung tumor of c-Myc transgenic mice, which suggests arginine-dependent tumor growth. Arginase-1 is expressed primarily in liver cells and plays an important role in the urea cycle. Besides microarray analysis, overexpression of Arg1 was obserevd in reverse transcription-polymerase chain reaction (RT-PCR) analysis and conformation of its protein expression in western blotting (see Figure 1 and Table 2 of Publication III). Furthermore, induced expression of Arg1 is associated with poor survival in human lung cancer patients (see Supplementary Table S9 and Figure 8 of Publication III). It is the topic of intense research to target arginine-dependent cancers. In this regard, arginine deprivation via induction of arginine-degrading/reducing enzymes such as arginine deiminase will regulate the arginine metabolome in cancer; thereby, it shows a novel strategy against metabolites for the treatment of arginine auxotrophy in lung cancers (Phillips MM et al. 2013, PMID: 24453997).
Fatty acid synthase (FASN) is a key metabolic multienzyme (multifunctional protein) that catalyzes the synthesis of the 16-carbon saturated fatty acid palmitate from the acetyl-CoA and malonyl-CoA in the presence of NADPH. Fatty acids are integral components of pulmonary surfactant, which is comprised of phospholipids and specific proteins and essential for normal functioning of lung. In PLACs, c-Myc responsive Fasn expression was induced by >3-fold. In earlier research, overexpression of FASN gene was observed in alveolar type II cells of pulmonary adenomas for producing pulmonary surfactants (Voelker DR et al. 1976, PMID: 10854) and was regulated by hormone, one of the possible regulators, in type II alveolar epithelial cells of human fetal lung (Wagle S et al. 1999, PMID: 10444533). Additionally, FASN is overexpressed in multiple cancers including lung cancer and is a promising target to selectively inhibit its activity for treatment of cancer (Orita H. et al. 2007, PMID: 18056164). A recent study reported that FASN promote NSCLC growth and chemoresistance by inducing expression of PKM2 and enhancing aerobic glycolysis, i.e. the Warburg Effect.
Spermidine synthase is a part of polyamine-biosynthetic pathway and using decarboxylated S-adenosylmethionine (dcSAM), it catalyzes the conversion of putrescine to spermidine in the final step of spermidine biosynthesis. Gene codes for spermidine synthase (Srm) was up-regulated by >5-fold in PLACs. This significant finding of Srm is growing evidence for c-Myc in regulating genes of polyamine metabolism as reported earlier in our research article (Ciribilli Y et al. 2015, PMID: 26427040). The intracellular concentration of polyamines is tightly regulated and metabolism of polyamines is frequently dysregulated for tumor cell growth; induced expression of enzymes involved in biosynthesis of polyamines has been associated with many cancers including lung cancer and has implications for chemotherapy and chemoprevention (Luk GD et al. 1981, PMID: 6264474, Nowotarski SL et al. 2013, PMID: 23432971,). In addition to arginase 1 and spermidine synthase, other polyamine metabolic genes such as L-ornithine decarboxylase 1 and S-adenosylmethionine decarboxylase 1 & 2 were significantly (P < 0.001) up-regulated by nearly 2-fold, nevertheless did not qualify the threshold criteria (3-fold) set for Table 1 of Publication III. Additionally, the renaissance of polyamine metabolism inhibitors in cancer treatment was highlighted in a perspective article of lung cancer research (Gautschi O. 2010, PMID: 20199972). Apart from targeting ornithine decarboxylase, spermidine synthase that is up-regulated in Myc-induced cancer is a promising target for the treatment of B-cell lymphomas (Forshell TP et al. 2010, PMID: 20103729, Gerner EW. 2010, PMID: 20103728).
Importantly, induced expression of Arg1, Fasn, Hk2 and Shmt1 were also observed in reverse transcription-polymerase chain reaction (RT-PCR) analysis and conformation of its protein expression in western blotting (see Figure 1 and Table 2 of Publication III). This confirms the significantly induced expression of these four genes in PLACs of c-Myc transgenic mice.
Elevated ribosome biogenesis in c-Myc induced lung cancer
c-MYC transcriptionally regulate the RNAs and protein components of ribosomes for protein synthesis, gene products essential for the processing of ribosomal RNA and the nuclear export of ribosomal subunits (van Riggelen J et al. 2010, PMID: 20332779); thereby, c-MYC is a regulator of ribosome biogenesis and dysregulation of ribosome biogenesis may play an important role in tumorigenesis (van Riggelen J et al. 2010, PMID: 20332779). Accordingly, several genes code for ribosome and associated with ribosome biogenesis were significantly up-regulated in lung tumors of c-Myc transgenic mice (Table1 of Publication III, and Figure 10). The ribosome biogenesis is the target of interest for several chemotherapeutics based cancer treatments (Bruno PM et al. 2017, PMID: 28263311).
Nucleophosmin/B23 (Npm1) codes for protein that participates in various cellular functions, including ribosome biogenesis and protein synthesis, DNA replication, centrosome duplication and cell proliferation. In addition to this, NPM1 together with several ribosomal proteins are transcriptional targets of MYC (Zeller KI et al. 2001, PMID: 11604407, Grisendi S et al. 2006, PMID: 16794633). As another function, up-regulation of nucleophosmin 1 has been observed to inhibit p53-mediated cellular senescence in colon cancer (Wong JC et al. 2013, PMID: 23536448). In PLACs, a significant 4-fold up-regulation of nucleophosmin 1 (Npm1) was identified and predicted as one of the seven potential master regulators (see Figure 8). In regards to function as ribosome processing and assembly, this nucleolar phosphoprotein acts as a molecular chaperone and preventing the aggregation of proteins within the nucleolus (Grisendi S et al. 2006, PMID: 16794633). However the Npm1 protein is frequently up-expressed in various solid tumors, but translocations are specifically observed in leukemias (Grisendi S et al. 2006, PMID: 16794633, Jeong EG et al. 2007, PMID: 17504301). Notably, a recent report demonstrated that YTR107-mediated targeting of NPM1 reduces DNA double-strand break repair is a promising radiosensitization approach for NSCLC therapy (Sekhar KR et al. 2014, PMID: 25035215). c-Myc DNA binding activity at gene specific promoter of Npm1 and Npm3 was supported by various experimental techniques data, which includes the strong EMSA bands (Figure 5 of Publication III) and independent ChIP-seq results (Supplementary Table S7 of Publication III).
Another gene codes for ribosome biogenesis is nucleolin/C23 (Ncl), a nucleolar phosphoprotein up-regulated in PLACs and was predicted as a master regulator (see Figure 8), was reported as a transcriptional target of c-Myc (Greasley PJ et al. 2000, PMID: 10606642). Over expression of nucleolin is observed in various cancers, and a research reported that expression level of nucleolin positively correlates with DNA damage repair (i.e. DNA-dependent protein kinases); therefore, nucleolin could serve as a promising treatment target as well as a prognostic factor for human NSCLC (Xu JY et al. 2016, PMID: 26846099).
Gene overexpression for DNA repair, genome stability and chromatin remodeling
As given in Table 1 of Publicatiob III and Figure 10, this suggests c-Myc influences DNA- base excision repair (BER) and non-homologous end joining (NHEJ) of DNA double-strand breaks. In this regards, genes coding for DNA-BER enzymes were up-regulated including apurinic/apyrimidinic endonuclease 1 (Apex1) and replication factor C subunit 4 (Rfc4). In addition, genes codes for base excision repair enzymes such as Rfc5, flap structure-specific endonuclease 1 (Fen1) and DNA polymerase delta interacting protein 2 (Poldip2) were significantly (P < 0.001) up-regulated by nearly 2-fold, however did not pass the threshold criteria (3-fold) set for Table 1 of Publication III. Besides BER, in support of angiogenesis and tumor progression, Apex1 also increases the DNA binding activity of several transcription factors and it could be a potential target for the consolidation of cisplatin-based chemotherapy in NSCLC patients (Wang D et al. 2009, PMID: 19324449). Importantly, the gene code for DNA topoisomerase II alpha (Top2a) is strongly up-regulated in PLACs by > 10-fold and 7-fold in small and large tumors, respectively. It is well known nuclear enzyme that catalyzes the transient breaking and rejoining of double strands of DNA and permits alteration in DNA topology. Importantly, high expression of Top2a is frequently detected in highly proliferative cells including NSCLC (Giaccone G et al. 1995, PMID: 8547322) and promising targets for anticancer agents (such as anthracyclines) that binds and blocks the activity of TopIIα. In addition, a positive correlation between the expression of cell-proliferation markers TopIIα and Ki67 has been reported in NSCLC patients where TopIIα expression can be used as a prognostic biomarker for chemotherapy (Yan S et al. 2010, PMID: 21067592). Accordingly, genes code for Ki67 protein (Publication II) and Ki67 interacting protein were strongly up-regulated in PLACs (Table 1 of Publication III). Furthermore, in response to DNA double strand breaks, gene code for and NHEJ repair enzymes such as double strand break repair nuclease Mre11a, a member of Mre11-Rad50-NBS1 complex, and ATP-dependent DNA helicase II 80 KDa subunit (KU80 or Xrcc5) and 70 KDa Subunit (KU70 or Xrcc6) were significantly up-regulated in PLACs.
Furthermore, the altered expression of genes for the structural changes in nucleosome and altered access to nucleosome-associated DNA for replication, transcription and repair were observed, and includes up-regulated linker histone H1fx and the down-regulated core histone H2b1. Induced expression of Smarcc1 was also observed and coded protein shows helicase and ATPase activities and due to chromatin remodeling, it participates in transcriptional activation and repression of genes. Contrary, special AT-rich sequence binding protein 1 (SATB1) that is a nuclear matrix-associated protein participates in chromatin remodeling and tissue-specific gene expression (Cai S et al. 2003, PMID: 12692553), and a leucine-rich acidic nuclear protein (ANP32A) that is a tumor suppressor and inhibitor of histone acetyl-transferases (Seo SB et al. 2002, PMID: 11830591) were down-regulated at the transcript level. Note, it was reported earlier that lost expression of SATB1 is a promising marker of poor survival in lung cancer (Selinger CI et al. 2011, PMID: 21597389) and siRNA mediated silencing of SATB1 inhibits the proliferation and invasion in lung cancer cells (Huang B et al. 2013, PMID: 23379909). Likewise, ANP32A is targeted by microRNA-21 (Schramedei K et al. 2011, PMID: 21317927). Altogether, in response to c-Myc-hyperactivity, altered expression of SATB1 and ANP32A will affect chromatin remodeling to initiate undue expression of genes.
Regulatory gene networks
In promoters of up-regulated genes in PLACs of c-Myc transgenic mice, the construction of composite module was defined by the genetic algorithm that significantly discriminates between normal and oncogenic c-Myc activity. Moreover, a search for identification of co-occupied TF-binding sites including c-Myc and its neighboring partner(s) in gene-specific promoters was performed; as re result, we propose c-Myc cooperativity with E2F1/E2F3-TFDP1 for up-regulated genes in PLACs, therefore defining molecular rules for transcriptional responses in c-Myc-targeted promoters. Notably, the proposed composite module majorly regulates genes associated with metabolism including nucleotide biosynthesis and DNA metabolism (see Supplementary Table S5 in Publication III). In this support, a study surmised that the DNA replication machinery as well as nucleotide pool regulation was transcriptionally regulation by both the factors i.e. MYC and E2F (Liu YC et al. 2008, PMID: 18628958). These two transcription factors contain different binding sites in promotes of same nucleotide genes
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