Nasopharyngeal carcinoma (NPC) is characterized by a high rate of local invasion and early distant metastasis. Increasing evidence indicates that epigenetic abnormalities play important roles in NPC development. However, the epigenetic mechanisms underlying NPC metastasis remain unclear. Here we investigate aberrantly methylated transcription factors in NPC tissues, and we identify the HOP homeobox HOPX as the most significantly hypermethylated gene. Consistently, we find that HOXP expression is downregulated in NPC tissues and NPC cell lines. Restoring HOPX expression suppresses metastasis and enhances chemosensitivity of NPC cells. These effects are mediated by HOPX-mediated epigenetic silencing of SNAIL transcription through the enhancement of histone H3K9 deacetylation in the SNAIL promoter. Moreover, we find that patients with high methylation levels of HOPX exhibit poor clinical outcomes in both the training and validation cohorts. In summary, HOPX acts as a tumour suppressor via the epigenetic regulation of SNAIL transcription, which provides a novel prognostic biomarker for NPC metastasis and therapeutic target for NPC treatment.

Approximately 15% of cancers use homologous recombination for alternative lengthening of telomeres (ALT). How the initiating genomic lesions invoke homology-directed telomere synthesis remains enigmatic. Here, we show that distinct dependencies exist for telomere synthesis in response to replication stress or DNA double-strand breaks (DSBs). RAD52 deficiency reduced spontaneous telomeric DNA synthesis and replication stress-associated recombination in G2, concomitant with telomere shortening and damage. However, viability and proliferation remained unaffected, suggesting that alternative telomere recombination mechanisms compensate in the absence of RAD52. In agreement, RAD52 was dispensable for DSB-induced telomere synthesis. Moreover, a targeted CRISPR screen revealed that loss of the structure-specific endonuclease scaffold SLX4 reduced the proliferation of RAD52null ALT cells. While SLX4 was dispensable for RAD52-mediated ALT telomere synthesis in G2, combined SLX4 and RAD52 loss resulted in elevated telomere loss, unresolved telomere recombination intermediates, and mitotic infidelity. These findings establish that RAD52 and SLX4 mediate distinct postreplicative DNA repair processes that maintain ALT telomere stability and cancer cell viability.

G-quadruplexes are specialized secondary structures in nucleic acids that possess significant conformational polymorphisms. The precise G-quadruplex conformations in vivo and their relevance to biological functions remain controversial and unclear, especially for telomeric G-quadruplexes. Here, we report a novel single-chain variable fragment (scFv) antibody, D1, with high binding selectivity for parallel G-quadruplexes in vitro and in vivo. Genome-wide chromatin immunoprecipitation using D1 and deep-sequencing revealed the consensus sequence for parallel G-quadruplex formation, which is characterized by G-rich sequence with a short loop size (<3 nt). By using D1, telomeric parallel G-quadruplex was identified and its formation was regulated by small molecular ligands targeting and telomere replication. Together, parallel G-quadruplex specific antibody D1 was found to be a valuable tool for determination of G-quadruplex and its conformation, which will prompt further studies on the structure of G-quadruplex and its biological implication in vivo.

The recent epidemic of obesity has been associated with a sharp rise in the incidence of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism(s) remains poorly described and effective therapeutic approaches against NAFLD are lacking. The results establish that microRNA-378 facilitates the development of hepatic inflammation and fibrosis and suggests the therapeutic potential of microRNA-378 inhibitor for the treatment of NAFLD.

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide and therapeutic agents for this malignancy are lacking. MicroRNAs play critical roles in carcinogenesis and present tremendous therapeutic potential. Here we report that microRNA-206 is a robust tumor suppressor that plays important roles in the development of HCC by regulating cell cycle progression and cMet signaling pathway. MicroRNA-206 was under-expressed in livers of two HCC mouse models, human individuals bearing HCC, and human HCC cell lines. Combining bioinformatic prediction and molecular and cellular approaches, we identified cMET (Met proto-oncogene), CCND1, and CDK6 as functional targets of microRNA-206. By inhibiting expression of cMET, CCND1 and CDK6, microRNA-206 delayed cell cycle progression, induced apoptosis and impaired proliferation of three distinct human HCC cell lines. Systemic administration of microRNA-206 completely prevented HCC development in both cMyc and AKT/Ras HCC mice, while 100% of control mice died from lethal tumor burdens. Conversely, re-introduction of cMet or Cdk6 into livers of cMyc and AKT/Ras HCC mice recovered growth of HCC inhibited by microRNA-206. These results strongly suggested that cMet and Cdk6 were two functional targets that mediated the inhibitory effect of microRNA-206 on the development of HCC. MicroRNA-206 overexpression demonstrated a profound therapeutic effect on HCC in xenograft and cMyc HCC mice. In summary, this study defines a potentially critical role of microRNA-206 in preventing the growth of HCC, and suggests its use as a potential therapeutic strategy for this malignancy.