Cancer up-regulated drug resistant (CUDR) is a novel non-coding RNA gene. Herein, we demonstrate excessive CUDR cooperates with excessive CyclinD1 or PTEN depletion to accelerate liver cancer stem cells growth and liver stem cell malignant transformation in vitro and in vivo. Mechanistically, we reveal the decrease of PTEN in cells may lead to increase binding capacity of CUDR to CyclinD1. Therefore, CUDR-CyclinD1 complex loads onto the long noncoding RNA H19 promoter region that may lead to reduce the DNA methylation on H19 promoter region and then to enhance the H19 expression. Strikingly, the overexpression of H19 increases the binding of TERT to TERC and reduces the interplay between TERT with TERRA, thus enhancing the cell telomerase activity and extending the telomere length. On the other hand, insulator CTCF recruits the CUDR-CyclinD1 complx to form the composite CUDR-CyclinD1-insulator CTCF complex which occupancied on the C-myc gene promoter region, increasing the outcome of oncogene C-myc. Ultimately, excessive TERT and C-myc lead to liver cancer stem cell and hepatocyte-like stem cell malignant proliferation. To understand the novel functions of long noncoding RNA CUDR will help in the development of new liver cancer therapeutic and diagnostic approaches.

Changes in histone lysine methylation status have been observed during cancer formation. JMJD2A protein is a demethylase that is overexpressed in several tumors. Herein, our results demonstrate that JMJD2A accelerates malignant progression of liver cancer cells in vitro and in vivo. Mechanistically, JMJD2A promoted the expression and mature of pre-miR372 epigenetically. Notably, miR372 blocks the editing of 13th exon-introns-14th exon and forms a novel transcript( JMJD2AΔ) of JMJD2A. In particular, JMJD2A inhibited P21(WAF1/Cip1) expression by decreasing H3K9me3 dependent on JMJD2AΔ. Thereby, JMJD2A could enhance Pim1 transcription by suppressing P21(WAF1/Cip1). Furthermore, through increasing the expression of Pim1, JMJD2A could facilitate the interaction among pRB, CDK2 and CyclinE which prompts the transcription and translation of oncogenic C-myc. Strikingly, JMJD2A may trigger the demethylation of Pim1. On the other hand, Pim1 knockdown and P21(WAF1/Cip1) overexpression fully abrogated the oncogenic function of JMJD2A. Our observations suggest that JMJD2A promotes liver cancer cell cycle progress through JMJD2A-miR372-JMJD2AΔ-P21WAF1/Cip1-Pim1-pRB-CDK2-CyclinE-C-myc axis. This study elucidates a novel mechanism for JMJD2A in liver cancer cells and suggests that JMJD2A can be used as a novel therapeutic targets of liver cancer.

microRNAs (miRNAs) are short non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miR675, embedded in H19's first exon, had been linked to the development of human cancers. Herein, we demonstrate miR675 overexpression promotes and silencing miR675 attenuated liver cancer cell growth in vitro and in vivo. Mechanistically, miR675 inhibits the heterochromatin1 isoform HP1α expression in human liver cancer cells which causes a dramatically decrease of the total histone H3 lysine 9 trimethylation (H3K9me3) , histone H3 lysine 27 trimethylation (H3K27me3) and a increase of histone H3 lysine 27 acetylation(H3K27Ac).Notably, a significant reduction of the H3K9me3 and H3K27me3 and the increment of H3K27Ac occupancy on the promoter region of EGR1 triggers EGR1 transcription, translation, sumoylation and activation which upregulates lincRNA H19. Strikingly, H19 may induce and activate tumor-specific pyruvate kinase M2 (PKM2) which is essential for the Warburg effect in its dimer and for gene expression in its teramer during tumorigenesis. Our results imply that miR675 is involved in the epigenetic regulation of H3K9me3, H3k27me3 and H3K27Ac for gene expression and function during hepatocarcinogenesis (e.g.C-myc,Pim1,Ras,CyclinD1,RB1).These findings sheds light on the significance of miR675-HP1α-EGR1-H19-PKM2 cascade signaling pathway in liver cancer.

P53 is frequently mutated in human tumors as a novel gain-of-function to promote tumor development. Although dimeric (M340Q/L344R) influences on tetramerisation on site-specific post-translational modifications of p53, it is not clear how dimeric (M340Q/L344R) plays a role during hepatocarcinogenesis. Herein, we reveal that P53 (N340Q/L344R) promotes hepatocarcinogenesis through upregulation of PKM2. Mechanistically, P53 (N340Q/L344R) forms complex with CUDR and the complex binds to the promoter regions of PKM2 which enhances the expression, phosphorylation of PKM2 and its polymer formation. Thereby, the polymer PKM2 (tetramer) binds to the eleventh threonine on histone H3 that increases the phosphorylation of the eleventh threonine on histone H3 (pH3T11). Furthermore, pH3T11 blocks HDAC3 binding to H3K9Ac that prevents H3K9Ac from deacetylation and stabilizes the H3K9Ac modification. On the other hand, it also decreased tri-methylation of histone H3 on the ninth lysine (H3K9me3) and increases one methylation of histone H3 on the ninth lysine (H3K9me1). Moreover, the combination of H3K9me1 and HP1 α forms more H3K9me3-HP1α complex which binds to the promoter region of Pim1, enhancing the expression of Pim1 that enhances the expression of TERT, oncogenic lncRNA HOTAIR and reduces the TERRA expression. Ultimately, P53 (N340Q/L344R) accerlerates the growth of liver cancer cells Hep3B by activating telomerase and prolonging telomere through the cascade of P53 (N340Q/L344R)-CUDR-PKM2-pH3T11- (H3K9me1-HP1α)-Pim1- (TERT-HOTAIR-TERRA). Understanding the novel functions of P53 (N340Q/L344R) will help in the development of new liver cancer therapeutic approaches that may be useful in a broad range of cancer types.

Cancer stem cells are associated with tumor recurrence. IKK is a protein kinase that is composed of IKKα, IKKβ, IKKγ. Herein, we demonstrate that IKKα plus IKKβ promoted and IKKγ inhibited liver cancer stem cell growth in vitro and in vivo. Mechanistically, IKKα plus IKKβ enhanced and IKKγ inhibited the interplay among HP1α, HP1β and HP1γ that competes for the interaction among HP1α, SUZ12, HEZ2. Therefore, IKKα plus IKKβ inhibited and IKKγ enhanced the activity of H3K27 methyltransferase SUZ12 and EZH2, which methylates H3K27 immediately sites on HOTAIR promoter region. Therefore, IKKα plus IKKβ increased and IKKγ decreased the HOTAIR expression. Strikingly, IKKα plus IKKβ decreases and IKKγ increases the HP1α interplays with DNA methyltransferase DNMT3b, which increases or decreases TERRA promoter DNA methylation. Thus IKKα plus IKKβ reduces and IKKγ increases to recruit TRF1 and RNA polymerase II deposition and elongation on the TERRA promoter locus, which increases or decreases TERRA expression. Furthermore, IKKα plus IKKβ decreases/increases and IKKγ increases/decreases the interplay between TERT and TRRRA/between TERT and TREC. Ultimately, IKKα plus IKKβ increases and IKKγ decreases the telomerase activity. On the other hand, at the telomere locus, IKKα plus IKKβ increases/drcreases and IKKγ decreases/increases TRF2, POT1, pPOT1, Exo1, pExo1, SNM1B, pSNM1B/CST-AAF binding, which keep active telomere regulatory genes and poised for telomere length. Strikingly, HOTAIR is required for IKKα plus IKKβ and IKKγ to control telomerase activity and telomere length. These observations suggest that HOTAIR operates the action of IKKα, IKKβ, IKKγ in liver cancer stem cells. This study provides a novel basis to elucidate the oncogenic action of IKKα, IKKβ, IKKγ and prompts that IKKα, IKKβ, IKKγ cooperate to HOTAR to be used as a novel therapeutic targets for liver cancer.

Long non-coding RNA HOTAIR predicts negative tumor prognosis and exhibits oncogenic activity. Herein, we demonstrate HOTAIR promotes human liver cancer stem cell malignant growth through downregulation of SETD2. Mechanistically, HOTAIR reduces the recuritment of the CREB, P300, RNA polII onto the SETD2 promoter region that inhibits SETD2 expression and its phosphorylation. Thereby, the SETD2 binding capacity to substrate histone H3 is weakened, triggering a reduction of trimethylation on histone H3 thirty-sixth lysine, and thereby the H3K36me3-hMSH2-hMSH6-SKP2 complex is also decreased. Strikingly, the complex occupancy on chromosome is depressed, preventing from mismatch DNA repair. While reducing the degradation capacity of Skp2 for aging histone H3 bound to damaged DNA, the aging histone repair is impaired. Furthermore, that the damaged DNA escaped to repair can causes microsatellite instability(MSI) and abnormal expression of cell cycle related genes that may trigger the hepatocarcinogenesis. This study provides evidence for HOTAIR to promote tumorigenesis via downregulating SETD2 in liver cancer stem cells.

Gene fusions play a critical role in some cancers and can serve as important clinical targets. In epithelial ovarian cancer (EOC), the contribution of fusions, especially by histological type, is unclear. We therefore screened for recurrent fusions in a histologically diverse panel of 220 EOCs using RNA sequencing. The Pipeline for RNA-Sequencing Data Analysis (PRADA) was used to identify fusions and allow for comparison with The Cancer Genome Atlas (TCGA) tumors. Associations between fusions and clinical prognosis were evaluated using Cox proportional hazards regression models. Nine recurrent fusions, defined as occurring in two or more tumors, were observed. CRHR1-KANSL1 was the most frequently identified fusion, identified in 6 tumors (2.7% of all tumors). This fusion was not associated with survival; other recurrent fusions were too rare to warrant survival analyses. One recurrent in-frame fusion, UBAP1-TGM7, was unique to clear cell (CC) EOC tumors (in 10%, or 2 of 20 CC tumors). We found some evidence that CC tumors harbor more fusions on average than any other EOC histological type, including high-grade serous (HGS) tumors. CC tumors harbored a mean of 7.4 fusions (standard deviation [sd] = 7.4, N = 20), compared to HGS EOC tumors mean of 2.0 fusions (sd = 3.3, N = 141). Few fusion genes were detected in endometrioid tumors (mean = 0.24, sd = 0.74, N = 55) or mucinous tumors (mean = 0.25, sd = 0.5, N = 4) tumors. To conclude, we identify one fusion at 10% frequency in the CC EOC subtype, but find little evidence for common (> 5% frequency) recurrent fusion genes in EOC overall, or in HGS subtype-specific EOC tumors.

MISIIR is a potential target for ovarian cancer (OC) therapy due to its tissue-specific pattern of expression. 3C23K is a novel therapeutic monoclonal anti-MISIIR antibody designed to recruit effector cells and promote cell death through ADCC (antibody dependent cell-mediated cytotoxicity). Our objective was to determine the tolerability and efficacy of 3C23K in OC patient-derived xenografts (PDX) and to identify factors affecting efficacy. Quantitative RT-PCR, immunohistochemistry (IHC), and flow cytometry were used to categorize MISIIR expression in established PDX models derived from primary OC patients. We selected two high expressing models and two low expressing models for in vivo testing. One xenograft model using an MISIIR over-expressing SKOV3ip cell line (Z3) was a positive control. The primary endpoint was change in tumor size. The secondary endpoint was final tumor mass. We observed no statistically significant differences between control and treated animals. The lack of response could be secondary to a number of variables including the lack of known biomarkers of response, the low membrane expression of MISIIR, and a limited ability of 3C23K to induce ADCC in PDX models. Further study is needed to determine the magnitude of ovarian cancer response to 3C23K and also if there is a threshold surface expression to predict response.

Chromatin is a highly organized and dynamic structure in eukaryotic cells. The change of chromatin structure is essential in many cellular processes, such as gene transcription, DNA damage repair and others. Anti-silencing function 1 (ASF1) is a histone chaperone that participates in chromatin higher-order organization and is required for appropriate chromatin assembly. In this study, we identified the E2 ubiquitin-conjugating enzyme RAD6 as an evolutionary conserved interacting protein of ASF1 in D. melanogaster and H. sapiens that promotes the turnover of ASF1A by cooperating with a well-known E3 ligase, MDM2, via ubiquitin-proteasome pathway in H. sapiens. Further functional analyses indicated that the interplay between RAD6 and ASF1A associates with tumorigenesis. Together, these data suggest that the RAD6-MDM2 ubiquitin ligase machinery is critical for the degradation of chromatin-related proteins.