High aerobic glycolysis not only provides energy to cancer cells, but also supports their anabolic growth. JMJD1A, a histone demethylase that specifically demethylates H3K9me1/2, is overexpressed in multiple cancers, including urinary bladder cancer (UBC). It is unclear whether JMJD1A could promote cancer cell growth through enhancing glycolysis. In this study, we found that downregulation of JMJD1A decreased UBC cell proliferation, colony formation and xenograft tumor growth. Knockdown of JMJD1A inhibited glycolysis by decreasing the expression of genes participated in glucose metabolism, including GLUT1, HK2, PGK1, PGM, LDHA and MCT4. Mechanistically, JMJD1A cooperated with hypoxia inducible factor 1α (HIF1α), an important transcription factor for glucose metabolism, to induce the glycolytic gene expression. JMJD1A was recruited to the promoter of glycolytic gene PGK1 to demethylate H3K9me2. However, the JMJD1A (H1120Y) mutant, which loses the demethylase activity, failed to cooperate with HIF1α to induce the glycolytic gene expression, and failed to demethylate H3K9me2 on PGK1 promoter, suggesting that the demethylase activity of JMJD1A is essential for its coactivation function for HIF1α. Inhibition of glycolysis through knocking down HIF1α or PGK1 decelerated JMJD1A-enhanced UBC cell growth. Consistent with these results, a positive correlation between JMJD1A and several key glycolytic genes in human UBC samples was established by analyzing a microarray-based gene expression profile. In conclusion, our study demonstrates that JMJD1A promotes UBC progression by enhancing glycolysis through coactivation of HIF1α, implicating that JMJD1A is a potential molecular target for UBC treatment.

Chronic infection of hepatitis B virus (HBV) is closely associated with the development of human hepatocellular carcinoma (HCC). HBV X protein (HBx) plays a key role in the progression of HCC. We recently found that amplified in breast cancer 1 (AIB1) protein is overexpressed in 68% of human HCC specimens and promotes HCC progression by enhancing cell proliferation and invasiveness. Given that both HBx and AIB1 play important oncogenic roles in HCC, we aimed to determine whether they could cooperatively promote human HCC development. Herein, we show that HBx‐positive HCC tissues had a higher level of AIB1 protein, compared to HBx‐negative HCC tissues. A positive correlation between HBx protein level and AIB1 protein level was established in HCC specimens. Without affecting its messenger RNA level, HBx induced a significant increase of the protein level of AIB1, which correlated with a significant extension of the half‐life of AIB1 protein. Mechanistically, HBx could interact with AIB1 to prevent the interaction between envelope protein 3 ubiquitin ligase F‐box and WD repeat domain containing 7 (Fbw7)α and AIB1, then inhibited the Fbw7α‐mediated ubiquitination and degradation of AIB1. In addition, reporter assays and chromatin immunoprecipitation assays revealed that both HBx and AIB1 were recruited to matrix metalloproteinase‐9 (MMP‐9) promoter to enhance MMP‐9 promoter activity cooperatively. Consistently, HBx and AIB1 cooperatively enhanced MMP‐9 expression in HepG2 cells, which, in turn, increased cell‐invasive ability. Conclusion: Our study demonstrates that HBx can stabilize AIB1 protein and cooperate with it to promote human HCC cell invasiveness, highlighting the essential role of the cross‐talk between HBx and AIB1 in HBV‐related HCC progression. (HEPATOLOGY 2012;56:1015–1024)

Background: Steroid receptor coactivator 1 (SRC-1) is a transcriptional coactivator. Results: SRC-1 promotes human hepatocellular carcinoma (HCC) cell proliferation by coactivating ␤-catenin to enhance c-Myc expression. Conclusion: SRC-1 plays an important role in HCC progression by enhancing Wnt/␤-catenin signaling. Significance: SRC-1 is a potential therapeutic molecular target for human HCC.

Aberrant activation of Notch signaling plays an essential role in colorectal cancer (CRC) progression. Amplified in breast cancer 1 (AIB1), also known as SRC-3 or NCOA3 is a transcriptional coactivator that promotes cancer cell proliferation and invasiveness. However AIB1 implication in CRC progression through enhancing Notch signaling is unknown. In this study we found that several CRC cell lines expressed high levels of AIB1, and knockdown of AIB1 decreased cell proliferation, colony formation and tumorigenesis of these CRC cells. Specifically, knockdown of AIB1 inhibited cell cycle progression at G1 phase by decreasing the mRNA levels of Cyclin A2, Cyclin B1, Cyclin E2 and Hes1. Furthermore, AIB1 interacted with Notch intracellular domain (NICD) and Mastermind-like 1 (MAMAL1) and was recruited to the Hes1 promoter to enhance Notch signaling. Downregulation of AIB1 also decreased CRC cell invasiveness in vitro and lung metastasis in vivo. Besides that, knockout of AIB1 in mice inhibited colon carcinogenesis induced by AOM/DSS treatment. The mRNA levels of Cyclin B1 and Hes5 were downregulated, but p27, ATOH1, and MUC2 were upregulated in the colon tumors from AIB1-deficient mice compared with those from wild-type mice. Thus our results signify the importance of AIB1 in CRC and demonstrate that AIB1 promotes CRC progression at least in part through enhancing Notch signaling, suggesting that AIB1 is a potential molecular target for CRC treatment.

BackgroundGeneral control non-depressible 5 (GCN5) is a crucial catalytic component of a transcriptional regulatory complex that plays important roles in cellular functions from cell cycle regulation to DNA damage repair. Although GCN5 has recently been implicated in certain oncogenic roles, its role in liver cancer progression remains vague.ResultsIn this study, we report that GCN5 was overexpressed in 17 (54.8 %) of 31 human hepatocellular carcinoma (HCC) specimens. Down-regulation of GCN5 inhibited HCC cell proliferation and xenograft tumor formation. GCN5 knockdown decreased the protein levels of the proliferation marker proliferating cell nuclear antigen (PCNA) and amplified in breast cancer 1 (AIB1), but increased the protein levels of cell cycle inhibitor p21Cip1/Waf1 in HepG2 cells. GCN5 regulated AIB1 expression, at least in part, by cooperating with E2F1 to enhance AIB1 transcription. Consistently, GCN5 expression was positively correlated with AIB1 expression in human HCC specimens in two GEO profile datasets.ConclusionSince AIB1 plays a promoting role in HCC progression, our results propose that GCN5 promotes HCC progression at least partially by regulating AIB1 expression. This study implicates that GCN5 might be a potential molecular target for HCC diagnosis and treatment.