Yiqun Jiang

Nuclear epidermal growth factor receptor interacts with transcriptional intermediary factor 2 to activate cyclin D1 gene expression triggered by the oncoprotein latent membrane protein 1

The epidermal growth factor receptor (EGFR), a ubiquitously expressed receptor tyrosine kinase, is an important factor in carcinogenesis. Transcriptional intermediary factor 2 (TIF2), a member of the p160 nuclear receptor co-activator gene family, is linked to the proliferation of cancer cells. However, the direct interplay between the EGFR and the nuclear receptors remains unclear. Our previous study demonstrated that nuclear EGFR could directly bind to the cyclin D1 promoter under the regulation of the oncoprotein latent membrane protein 1 (LMP1), but it also indicated that other factors are involved in the activation of target genes. In this study, we found that LMP1 upregulated the expression of TIF2 and promoted the interaction of EGFR with TIF2 in nasopharyngeal carcinoma. Furthermore, we demonstrated that the intact complex was linked with cyclin D1 promoter activity in an LMP1-dependent manner. The physiological functions of the intact complex were associated with cell proliferation and cell cycle progression. These findings suggest that TIF2 is a novel binding partner for nuclear EGFR and is involved in regulating its target gene expression.

Genome-wide distribution of DNA methylation and DNA demethylation and related chromatin regulators in cancer

DNA methylation plays an important role in the regulation of gene expression, as it is the first epigenetic modification to take place on a given DNA strand. Several factors may directly or indirectly regulate the dynamic distribution of DNA methylation and demethylation between intergenic and intragenic gene regions, thereby controlling gene expression. CpG islands have direct implications for the understanding of DNA methylation patterns in normal conditions and in some common disease states, including cancer. Here, we summarize several recent studies on the genome-wide distribution of DNA methylation and demethylation and their related factors, and we discuss the potential of DNA methylation and demethylation patterns to contribute to gene transcription patterns in tumorigenesis.

The ratio of FoxA1 to FoxA2 in lung adenocarcinoma is regulated by LncRNA HOTAIR and chromatin remodeling factor LSH

The lncRNA HOTAIR is a critical regulator of cancer progression. Chromatin remodeling factor LSH is critical for normal development of plants and mammals. However, the underlying mechanisms causing this in cancer are not entirely clear. The functional diversification of the FOXA1 and FOXA2 contributes to the target genes during evolution and carcinogenesis. Little is known about the ratio of FOXA1 to FOXA2 in cancer. We here found that both HOTAIR and LSH overexpression was significantly correlated with poor survival in patients with lung adenocarcinoma cancer (ADC). Also, the ratio of FOXA1 and FOXA2 is linked with poor survival in patients with lung ADC. HOTAIR regulates the ratio of FOXA1 to FOXA2 and migration and invasion. HOTAIR and the ratio of FOXA1 to FOXA2 are negatively correlated. HOTAIR knockdown inhibits migration and invasion. HOTAIR is associated with LSH, and this association linked with the binding of LSH in the promoter of FOXA1, not FOXA2. Targeted inhibition of HOTAIR suppresses the migratory and invasive properties. These data suggest that HOTAIR is an important mediator of the ratio of FOXA1 and FOXA2 and LSH involves in, and suggest that HOTAIR inhibition may represent a promising therapeutic option for suppressing lung ADC progression.

Repression of Hox genes by LMP1 in nasopharyngeal carcinoma and modulation of glycolytic pathway genes by HoxC8

Epstein-Barr virus (EBV) causes human lymphoid malignancies, and the EBV product latent membrane protein 1 (LMP1) has been identified as an oncogene in epithelial carcinomas such as nasopharyngeal carcinoma (NPC). EBV can epigenetically reprogram lymphocyte-specific processes and induce cell immortalization. However, the interplay between LMP1 and the NPC host cell remains largely unknown. Here, we report that LMP1 is important to establish the Hox gene expression signature in NPC cell lines and tumor biopsies. LMP1 induces repression of several Hox genes in part via stalling of RNA polymerase II (RNA Pol II). Pol II stalling can be overcome by irradiation involving the epigenetic regulator TET3. Furthermore, we report that HoxC8, one of the genes silenced by LMP1, has a role in tumor growth. Ectopic expression of HoxC8 inhibits NPC cell growth in vitro and in vivo, modulates glycolysis and regulates the expression of tricarboxylic acid (TCA) cycle-related genes. We propose that viral latency products may repress via stalling key mediators that in turn modulate glycolysis.

Chromatin Remodeling Factor LSH Drives Cancer Progression by Suppressing the Activity of Fumarate Hydratase

Chromatin modification is pivotal to the epithelial-mesenchymal transition (EMT), which confers potent metastatic potential to cancer cells. Here, we report a role for the chromatin remodeling factor lymphoid-specific helicase (LSH) in nasopharyngeal carcinoma (NPC), a prevalent cancer in China. LSH expression was increased in NPC, where it was controlled by the Epstein-Barr virus-encoded protein LMP1. In NPC cells in vitro and in vivo, LSH promoted cancer progression in part by regulating expression of fumarate hydratase (FH), a core component of the tricarboxylic acid cycle. LSH bound to the FH promoter, recruiting the epigenetic silencer factor G9a to repress FH transcription. Clinically, we found that the concentration of TCA intermediates in NPC patient sera was deregulated in the presence of LSH. RNAi-mediated silencing of FH mimicked LSH overexpression, establishing FH as downstream mediator of LSH effects. The TCA intermediates α-KG and citrate potentiated the malignant character of NPC cells, in part by altering IKKα-dependent EMT gene expression. In this manner, LSH furthered malignant progression of NPC by modifying cancer cell metabolism to support EMT. Cancer Res; 76(19); 5743-55. ©2016 AACR.

As a novel p53 direct target, bidirectional gene HspB2/αB-crystallin regulates the ROS level and Warburg effect.

Many mammalian genes are composed of bidirectional gene pairs with the two genes separated by less than 1.0kb. The transcriptional regulation and function of these bidirectional genes remain largely unclear. Here, we report that bidirectional gene pair HspB2/αB-crystallin, both of which are members of the small heat shock protein gene family, is a novel direct target gene of p53. Two potential binding sites of p53 are present in the intergenic region of HspB2/αB-crystallin. p53 up-regulated the bidirectional promoter activities of HspB2/αB-crystallin. Actinomycin D (ActD), an activator of p53, induces the promoter and protein activities of HspB2/αB-crystallin. p53 binds to two p53 binding sites in the intergenic region of HspB2/αB-crystallin in vitro and in vivo. Moreover, the products of bidirectional gene pair HspB2/αB-crystallin regulate glucose metabolism, intracellular reactive oxygen species (ROS) level and the Warburg effect by affecting metabolic genes, including the synthesis of cytochrome c oxidase 2 (SCO2), hexokinase II (HK2), and TP53-induced glycolysis and apoptosis regulator (TIGAR). The ROS level and the Warburg effect are affected after the depletion of p53, HspB2 and αB-crystallin respectively. Finally, we show that both HspB2 and αB-crystallin are linked with human renal carcinogenesis. These findings provide novel insights into the role of p53 as a regulator of bidirectional gene pair HspB2/αB-crystallin-mediated ROS and the Warburg effect.

LGR5 expression is controled by IKKα in basal cell carcinoma through activating STAT3 signaling pathway

Basal cell carcinomas (BCC) of the skin are the most common of human cancers. The noncanonical NF-κB pathway is dependent on IKKα. However, the role of IKKα in BCC has not been elucidated. We show here that IKKα is expressed in the nucleus in BCC and non-malignant diseases. Nuclear IKKα could directly bind to the promoters of inflammation factors and LGR5, a stem cell marker, in turn, upregulating LGR5 expression through activation of STAT3 signaling pathway during cancer progression. Activation of STAT3 signaling pathway contributes LGR5 expression in dependent of IKKα after the interplay between STAT3 and IKKα. Meanwhile knockdown of IKKα inhibits tumor growth and transition of epithelial stage to mescheme stage. Taken together, we demonstrate that IKKα functions as a bone fide chromatin regulator in BCC, whose promoted expression contributes to oncogenic transformation via promoting expression stemness- and inflammatory- related genes. Our finding reveals a novel viewpoint for how IKKα may involve in BCCs tumor progression in the inflammatory microenvironment.

Opposed expression of IKKα: loss in keratinizing carcinomas and gain in non-keratinizing carcinomas

The functional role of IKKα in vivo is pretty complicated, largely due to its diverse functions through cell autonomous and non-autonomous manners. In addition, most of the studies on IKKα were derived from animal models, whether these findings hold true in human tumors remain unclear. Here we examined the expression of IKKα in nasopharyngeal carcinoma, which includes non-keratinizing carcinoma and keratinizing squamous cell carcinoma, and lung squamous cell carcinoma with keratinization and non-keratinization. We demonstrated that IKKα expression was almost negative in keratinizing cancer and higher expression of IKKα was found in non-keratinizing cancer, and that IKKα expression correlateed with cellular differentiation of tumors in non-keratinizing nasopharyngeal carcinoma. These findings demonstrate that IKKα is diversely expressed in keratinizing and non-keratinizing carcinomas in the same type of cancer.

Chromatin Remodeling Factor LSH is Upregulated by the LRP6-GSK3β-E2F1 Axis Linking Reversely with Survival in Gliomas.

The signaling pathway-based stratification in chromatin modification could predict clinical outcome more reliably than morphology-alone-based classification schemes in gliomas. Here we reported a role of the chromatin-remodeling factor lymphoid-specific helicase (LSH) in gliomas. Among astrocytomas of grade I to III and glioblastoma of grade IV, LSH were almost completely expressed in all cases, and strongly correlated with astrocytomas progression and poor prognosis of patients with astrocytomas and glioblastoma. Ectopic expression of LSH promoted tumor formation. Up-regulation of transcription factor E2F1 in astrocytomas and glioblastoma was associated with the progression of gliomas and correlated with LSH expression. Chromatin immunoprecipitation (ChIP) analysis showed transcription factor E2F1 were recruited to the promoter region of LSH, and depletion of E2F1 decreased LSH expression and cell growth. Moreover, glycogen synthase kinase-3β (GSK-3β), an intact complex of E2F1, were also highly expressed in astrocytomas and linked with astrocytomas progression and poor prognosis of patients with astrocytomas and glioblastoma. Inhibition of GSK3β increased the enrichment of E2F1 to the LSH promoter, in turn, increased LSH expression. Lipoprotein receptor-related protein 6 (LRP6), an upstream regulator of GSK3β signaling pathway, was highly expressed in gliomas. Knockdown of LRP6 decreased LSH expression through decrease of recruitment of E2F1 to the LSH promoter leading to inhibition of cell growth. Taken together, this study reveals evidence demonstrating a mechanism by which upregulated promoted gliomas. A mechanistic link between LSH expression and activation of the LPR6/ GSK3β/E2F1 axis in gliomas illustrates a novel role of LSH in malignant astrocytomas and glioblastoma.

EGLN1/c-Myc Induced Lymphoid-Specific Helicase Inhibits Ferroptosis through Lipid Metabolic Gene Expression Changes

Ferroptosis is a newly discovered form of non-apoptotic cell death in multiple human diseases. However, the epigenetic mechanisms underlying ferroptosis remain poorly defined. First, we demonstrated that lymphoid-specific helicase (LSH), which is a DNA methylation modifier, interacted with WDR76 to inhibit ferroptosis by activating lipid metabolism-associated genes, including GLUT1, and ferroptosis related genes SCD1 and FADS2, in turn, involved in the Warburg effect. WDR76 targeted these genes expression in dependent manner of LSH and chromatin modification in DNA methylation and histone modification. These effects were dependent on iron and lipid reactive oxygen species. We further demonstrated that EGLN1 and c-Myc directly activated the expression of LSH by inhibiting HIF-1α. Finally, we demonstrated that LSH functioned as an oncogene in lung cancer in vitro and in vivo. Therefore, our study elucidates the molecular basis of the c-Myc/EGLN1-mediated induction of LSH expression that inhibits ferroptosis, which can be exploited for the development of therapeutic strategies targeting ferroptosis for the treatment of cancer.