Epigenetic regulation of the Warburg effect by H2B monoubiquitination.

Cancer cells reprogram their energy metabolic system from the mitochondrial oxidative phosphorylation (OXPHOS) pathway to a glucose-dependent aerobic glycolysis pathway. This metabolic reprogramming phenomenon is known as the Warburg effect, a significant hallmark of cancer. However, the detailed mechanisms underlying this event or triggering this reprogramming remain largely unclear. Here, we found that histone H2B monoubiquitination (H2Bub1) negatively regulates the Warburg effect and tumorigenesis in human lung cancer cells (H1299 and A549 cell lines) likely through controlling the expression of multiple mitochondrial respiratory genes, which are essential for OXPHOS. Moreover, our work also suggested that pyruvate kinase M2 (PKM2), the rate-limiting enzyme of glycolysis, can directly interact with H2B in vivo and in vitro and negatively regulate the level of H2Bub1. The inhibition of cell proliferation and nude mice xenograft of human lung cancer cells induced by PKM2 knockdown can be partially rescued through lowering H2Bub1 levels, which indicates that the oncogenic function of PKM2 is achieved, at least partially, through the control of H2Bub1. Furthermore, PKM2 and H2Bub1 levels are negatively correlated in cancer specimens. Therefore, these findings not only provide a novel mechanism triggering the Warburg effect that is mediated through an epigenetic pathway (H2Bub1) but also reveal a novel metabolic regulator (PKM2) for the epigenetic mark H2Bub1. Thus, the PKM2-H2Bub1 axis may become a promising cancer therapeutic target.

Mammalian sterile 20-like kinase 1 expression and its prognostic significance in patients with breast cancer.

Mammalian sterile 20-like kinase 1 (Mst1) is a major inhibitor of cell proliferation, and is involved in apoptosis, oncogenesis and organ growth via its ubiquitously encoded serine threonine kinase. Previous studies have demonstrated that Mst1 has a tumor suppressor function in human breast cancer. Mst1 deletion or mutation is associated with tumorigenesis, whereas Mst1 overexpression leads to tumor cell apoptosis and decreases proliferation of tumor cells. Our previous study reported the tumor suppressive function of Mst1, and debated Mst1 as a prognostic factor in human breast cancer. In the present study, Mst1 levels were measured in the plasma of patients in order to elucidate their association with overall and disease-free survival. The results of the present study indicated that Mst1 is a strong prognostic and predictive factor in human breast cancer and a promising anticancer target.

Overexpression of SYF2 promotes cell proliferation and correlates with poor prognosis in human breast cancer.

SYF2, a known cell cycle regulator, is reported to be involved in cell cycle arrest by interacting with cyclin-D-type binding protein 1. In the present study, we investigated the role of SYF2 in human breast cancer (BC) progression. SYF2 was highly upregulated in BC tissues and cell lines, as per Western blot and immunohistochemistry analysis. The SYF2 expression level had a significant correlation with the tumor grade and Ki-67 expression. In vitro starvation-refeeding experiment and SYF2-siRNA transfection assay demonstrated that SYF2 could promote proliferation of BC cells, while SYF2 knockdown resulted in cells cycle arrest at G1/S phase, reducing the cell growth rate of BC cells. These results indicated that SYF2 promotes human BC progression by accelerating the BC cells' proliferation. SYF2 could be a novel therapeutic target in human BC therapies.

Prognostic value of plasma levels of HIF-1a and PGC-1a in breast cancer.

Cellular adaptive mechanisms are crucial for tumorigenesis and a common feature in solid tumor progression. Hypoxia-inducible factor-1α (HIF-1α) facilitates the biological response to hypoxia, advancing angiogenesis and metastatic potential of the tumor. The peroxisome proliferator-activated receptor γ coactivators 1α (PGC-1α) enhances mitochondrial biogenesis, favored by migratory/invasive cancer cells. We conducted a prospective, long-term follow up study to determine whether HIF-1α and PGC-1α can be implemented as predictive biomarker in breast cancer. HIF-1α and PGC-1α plasma concentrations were measured in patients and in healthy controls by enzyme linked immune sorbent assay. Breast cancer patients had significantly higher HIF-1α and PGC-1α levels, which correlated with clinicopathological features, overall with more aggressive cancer characteristics. Disease free and overall survival of breast cancer patients with high HIF-1α and PGC-1α were significantly poorer than in patients with low plasma levels. In multivariate analysis, high amount of PGC-1α showed independent prognostic value. Our data suggests that HIF-1α and PGC-1α may be promising, noninvasive, biomarkers with a high potential for future clinical implication to identify subgroups of patients with poorer prognosis and to indicate early, subclinical metastasis.

Pyrosequencing quantified methylation level of BRCA1 promoter as prognostic factor for survival in breast cancer patient.

BRCA1 promoter methylation is an essential epigenetic transcriptional silencing mechanism, related to breast cancer (BC) occurrence and progression. We quantified the methylation level of BRCA1 promoter and evaluated its significance as prognostic and predictive factor. BRCA1 promoter methylation level was quantified by pyrosequencing in surgical cancerous and adjacent normal specimens from 154 BC patients. A follow up of 98 months was conducted to assess the correlation between BRCA1-methylation level vs. overall survival (OS) and disease free survival (DFS). The mean methylation level in BC tissues was significantly higher (mean 32.6%; median 31.9%) than in adjacent normal samples (mean 16.2%; median 13.0%) (P < 0.0001). Tumor stage (R = 0.6165, P < 0.0001) and size (R = 0.7328, P < 0.0001) were significantly correlated with the methylation level. Patients with unmethylated BRCA1 had a better OS and DFS compared to the methylated group (each P < 0.0001). BRCA1 promoter methylation level has a statistically significance on survival in BC patients (HazR = 1.465, P = 0.000) and is an independent prognostic factor for OS in BC patients (HazR = 2.042, P = 0.000). Patients with ductal type, HER2 negative, lymph node negative stage 1+2 tumors had a better OS and DFS. Classification of grades and molecular subtypes did not show any prognostic significance. Pyrosequencing is a precise and efficient method to quantify BRCA1 promoter methylation level, with a high potential for future clinical implication, as it identifies subgroups of patients with poorer prognosis.

Stromal fibroblast activation and their potential association with uterine fibroids (Review).

Uterine fibroids are the most common type of benign, gynecologic neoplasm and are the primary indication for performance of a hysterectomy, accounting for >200,000 hysterectomies annually in the USA. At present, females are younger and exhibit larger leiomyomas at the time of diagnosis. Cancer-associated fibroblasts in tumor microenvironments have emerged as an important target for cancer therapy. Repeated stimulation by infectious or non-infectious agents in the uterine tissues, including inflammation, mechanical forces or hypoxia, stimulate the resident fibroblasts to undergo specific activation and, thus, are significant in tumorigenesis. Furthermore, complex signaling pathways regulate the mechanisms of fibroblastic activation. The current review focuses on the molecular mechanisms of fibroblastic activation and the potential association with uterine leiomyoma pathogenesis, enabling an integrated pathogenic analysis for review of the therapeutic options.

Mutations of mitochondrial DNA as potential biomarkers in breast cancer.

BACKGROUND: Alterations of mitochondrial DNA (mtDNA) have been found in cancer patients, therefore informative mtDNA mutations could serve as biomarkers for the disease. MATERIALS AND METHODS: The two hypervariable regions HVR1 and HVR2 in the D-Loop region were sequenced in ten paired tissue and plasma samples from breast cancer patients. RESULTS: MtDNA mutations were found in all patients' samples, suggesting a 100% detection rate. Examining germline mtDNA mutations, a total of 85 mutations in the D-loop region were found; 31 of these mutations were detected in both tissues and matched plasma samples, the other 54 germline mtDNA mutations were found only in the plasma samples. Regarding somatic mtDNA mutations, a total of 42 mutations in the D-loop region were found in breast cancer tissues. CONCLUSION: Somatic mtDNA mutations in the D-loop region were detected in breast cancer tissues but not in the matched plasma samples, suggesting that more sensitive methods will be needed for such detection to be of clinical utility.

Epigenetic therapy for breast cancer.

Both genetic and epigenetic alterations can control the progression of cancer. Genetic alterations are impossible to reverse, while epigenetic alterations are reversible. This advantage suggests that epigenetic modifications should be preferred in therapy applications. DNA methyltransferases and histone deacetylases have become the primary targets for studies in epigenetic therapy. Some DNA methylation inhibitors and histone deacetylation inhibitors are approved by the US Food and Drug Administration as anti-cancer drugs. Therefore, the uses of epigenetic targets are believed to have great potential as a lasting favorable approach in treating breast cancer.

An overview of biomarkers for the ovarian cancer diagnosis.

Even though there are a lot of options in treating gynecological malignancies, ovarian cancer still remains a leading cause of death. Diagnosis at an early stage is the most important determinant of survival. Current diagnostic tools applied at clinics have had very limited success in early detection. Discovery of new diagnostic biomarkers/panels for early diagnosis of ovarian cancer is one of the main challenges of modern medicine. With the progress of techniques in genomics and proteomics, numerous molecular biomarkers/panels were identified and showed promise for ovarian cancer diagnosis, but still need further validation. This article summarizes various types of markers investigated by different strategies/technologies for the ovarian cancer diagnosis at present, including gene-, protein-based and emerging ovarian cancer indicators (such as microRNA-, metabolite-based). Before biomarker tests are translated for routine use, more researches, such as retrospective and prospective clinical trials, are needed to evaluate the overall clinical utility of the tests.