The Role of Transcription Factor YY1 in the Biology of Cancer.

The transcription factor Yin Yang 1 (YY1) is a ubiquitously expressed protein involved in several biological functions, including embryogenesis, differentiation, replication, and cellular proliferation. YY1 can both activate and repress transcription depending on its interactions with other transcription factors and co-factors. It affects the transcription of a large number of mammalian and viral genes. In this review, we focus on the role of YY1 in cancer biology, including its expression, function, regulation by other upstream factors, and some of its more significant downstream effectors. We also discuss its context-dependent and tumor-specific role in human cancer progression, roles as a prognostic marker, and how its interactions with other cancer-associated factors can be exploited to develop novel targeted therapies.

GON4L Drives Cancer Growth through a YY1-Androgen Receptor-CD24 Axis.

In principle, the inhibition of candidate gain-of-function genes defined through genomic analyses of large patient cohorts offers an attractive therapeutic strategy. In this study, we focused on changes in expression of CD24, a well-validated clinical biomarker of poor prognosis and a driver of tumor growth and metastasis, as a benchmark to assess functional relevance. Through this approach, we identified GON4L as a regulator of CD24 from screening a pooled shRNA library of 176 candidate gain-of-function genes. GON4L depletion reduced CD24 expression in human bladder cancer cells and blocked cell proliferation in vitro and tumor xenograft growth in vivo Mechanistically, GON4L interacted with transcription factor YY1, promoting its association with the androgen receptor to drive CD24 expression and cell growth. In clinical bladder cancer specimens, expression of GON4L, YY1, and CD24 was elevated compared with normal bladder urothelium. This pathway is biologically relevant in other cancer types as well, where CD24 and the androgen receptor are clinically prognostic, given that silencing of GON4L and YY1 suppressed CD24 expression and growth of human lung, prostate, and breast cancer cells. Overall, our results define GON4L as a novel driver of cancer growth, offering new biomarker and therapeutic opportunities. Cancer Res; 76(17); 5175-85. ©2016 AACR.

Multi-gene expression predictors of single drug responses to adjuvant chemotherapy in ovarian carcinoma: predicting platinum resistance.

Despite advances in radical surgery and chemotherapy delivery, ovarian cancer is the most lethal gynecologic malignancy. Standard therapy includes treatment with platinum-based combination chemotherapies yet there is no biomarker model to predict their responses to these agents. We here have developed and independently tested our multi-gene molecular predictors for forecasting patients' responses to individual drugs on a cohort of 55 ovarian cancer patients. To independently validate these molecular predictors, we performed microarray profiling on FFPE tumor samples of 55 ovarian cancer patients (UVA-55) treated with platinum-based adjuvant chemotherapy. Genome-wide chemosensitivity biomarkers were initially discovered from the in vitro drug activities and genomic expression data for carboplatin and paclitaxel, respectively. Multivariate predictors were trained with the cell line data and then evaluated with a historical patient cohort. For the UVA-55 cohort, the carboplatin, taxol, and combination predictors significantly stratified responder patients and non-responder patients (p = 0.019, 0.04, 0.014) with sensitivity = 91%, 96%, 93 and NPV = 57%, 67%, 67% in pathologic clinical response. The combination predictor also demonstrated a significant survival difference between predicted responders and non-responders with a median survival of 55.4 months vs. 32.1 months. Thus, COXEN single- and combination-drug predictors successfully stratified platinum resistance and taxane response in an independent cohort of ovarian cancer patients based on their FFPE tumor samples.

In vitro transcriptomic prediction of hepatotoxicity for early drug discovery.

Liver toxicity (hepatotoxicity) is a critical issue in drug discovery and development. Standard preclinical evaluation of drug hepatotoxicity is generally performed using in vivo animal systems. However, only a small number of preselected compounds can be examined in vivo due to high experimental costs. A more efficient yet accurate screening technique that can identify potentially hepatotoxic compounds in the early stages of drug development would thus be valuable. Here, we develop and apply a novel genomic prediction technique for screening hepatotoxic compounds based on in vitro human liver cell tests. Using a training set of in vivo rodent experiments for drug hepatotoxicity evaluation, we discovered common biomarkers of drug-induced liver toxicity among six heterogeneous compounds. This gene set was further triaged to a subset of 32 genes that can be used as a multi-gene expression signature to predict hepatotoxicity. This multi-gene predictor was independently validated and showed consistently high prediction performance on five test sets of in vitro human liver cell and in vivo animal toxicity experiments. The predictor also demonstrated utility in evaluating different degrees of toxicity in response to drug concentrations, which may be useful not only for discerning a compound's general hepatotoxicity but also for determining its toxic concentration.

The relationship of palliative transurethral resection of the prostate with disease progression in patients with prostate cancer.

OBJECTIVES: To test, in a prostate-cancer population-based database, the validity of the finding that in single-institution series, palliative transurethral resection of prostate (TURP) is associated with an increased risk of progression. PATIENTS AND METHODS: Using the Surveillance Epidemiology and END Results Registry, we identified men who had a TURP subsequent to their diagnosis of prostate cancer, from 1998 or 1999. The outcome of interest was disease progression, as defined by the initiation of androgen-deprivation therapy or procedures indicating progressive urinary obstruction. Multivariable logistic regression analysis was used to assess the adjusted odds of signal events related to disease progression adjusting for the concurrent effect of the covariates. RESULTS: There were 29,361 men with prostate cancer and 2742 (9.3%) had a TURP after the diagnosis. These men had a mean age of 75 years and were unlikely to undergo definitive primary treatment. Men receiving TURP were more likely to undergo orchidectomy than men who did not have a TURP (odds ratio 1.64; 95% confidence interval 1.03-2.60) even after adjusting for differences in cancer-directed treatment, tumour stage and grade, prostate-specific antigen level, race, and age at diagnosis. These men were also more likely to have malignant urinary obstruction (ureteric and bladder outlet) than were men who did not have TURP. CONCLUSION: The requirement for TURP is an adverse prognostic marker even when this is adjusted for classical tumour characteristics. Although the exact reasons for this finding are unclear, consideration should be given to adjuvant treatment in patients undergoing TURP.

Complementary and alternative medicine modality use and beliefs among African American prostate cancer survivors.

PURPOSE/OBJECTIVES: To examine the cultural beliefs and attitudes of African American prostate cancer survivors regarding the use of complementary and alternative medicine (CAM) modalities. RESEARCH APPROACH: Mixed methods with primary emphasis on a phenomenology approach. SETTING: In-person interviews in participants' homes and rural community facilities. PARTICIPANTS: 14 African American men diagnosed with and treated for prostate cancer. METHODOLOGIC APPROACH: Personal interviews using a semistructured interview guide. MAIN RESEARCH VARIABLES: Prostate cancer, CAM, African American men's health, culture, herbs, prayer, spirituality, and trust. FINDINGS: All participants used prayer often; two men used meditation and herbal preparations. All men reported holding certain beliefs about different categories of CAM. Several men were skeptical of CAM modalities other than prayer. Four themes were revealed: importance of spiritual needs as a CAM modality to health, the value of education in relation to CAM, importance of trust in selected healthcare providers, and how men decide on what to believe about CAM modalities. CONCLUSIONS: Prayer was a highly valued CAM modality among African American prostate cancer survivors as a way to cope with their disease. Medical treatment and trust in healthcare providers also were found to be important. INTERPRETATION: Most participants were skeptical of CAM modalities other than prayer. Participants expressed a strong belief in spirituality and religiosity in relationship to health and their prostate cancer. Participants' trust in their healthcare providers was important. Healthcare providers must understand how African Americans decide what to believe about CAM modalities to improve their health. This research provided valuable information for future development of culturally sensitive communication and infrastructural improvements in the healthcare system.

Impact of a novel neoadjuvant and adjuvant hormone-deprivation approach on quality of life, voiding function, and sexual function after prostate brachytherapy.

BACKGROUND: Data demonstrate a benefit from neoadjuvant and adjuvant hormone-deprivation therapy with luteinizing hormone-releasing hormone agonists in patients who are treated with radiotherapy for localized prostate carcinoma; however, this approach has detrimental effects on quality of life (QOL). A cross-sectional study was undertaken to evaluate the impact on QOL, voiding function, and sexual function of an alternative hormone-deprivation approach. METHODS: Three hundred fifty patients with clinical T1c-T2b prostate carcinoma were treated from March 1997 to August 2000 either with palladium 103 brachytherapy (BTM) without hormone therapy or with 8 months of adjuvant and neoadjuvant hormone-deprivation therapy with an antiandrogen and finasteride (BTM+H), were mailed the Functional Assessment of Cancer Therapy (FACT) global well being QOL instrument (FACT-G), the American Urological Association symptom score (AUASS), and specific items addressing urinary control and sexual function from validated instruments. Differences between treatment groups were assessed as a function of time since treatment. RESULTS: Seventy-two percent of patients responded to the questionnaire. No differences in overall FACT-G scores, AUASS scores, or AUASS subscale scores between the BTM group and the BTM+H group were found. The BTM+H group initially had lower personal well being FACT-G subscale scores, more urinary incontinence, and lower odds of attaining an erection sufficient for intercourse initially, although these differences disappeared with longer follow-up. CONCLUSIONS: The use of neoadjuvant and adjuvant antiandrogen and finasteride with brachytherapy is associated with QOL equal to that of brachytherapy alone for the treatment of patients with localized prostate carcinoma, allowing the advantages of hormone manipulation in terms of tumor control without its downside.

Gene profiling and promoter reporter assays: novel tools for comparing the biological effects of botanical extracts on human prostate cancer cells and understanding their mechanisms of action.

The use of botanical mixtures is commonplace in patients with prostate cancer, yet the majority of these products have not been rigorously tested in clinical trials. Here we use PC-SPES, a combination of eight herbs that has been shown to be effective in clinical trials in patients with prostate cancer, as a model system to demonstrate 'proof of principle' as to how gene expression profiling coupled with promoter assays can evaluate the effect of herbal cocktails on human prostate cancer. In addition, we demonstrate how such approaches may be used for standardization of herbal extract activity by comparing the gene profile of PC-SPES with that of PC-CARE, a product with a similar herbal composition. Since prior studies have shown that PC-SPES contains estrogenic organic compounds, and such compounds are known to affect prostate cancer, an important issue is whether these are the primary drivers of the gene profile. Our data suggest that gene expression profiles of LNCaP human prostate cancer cells in response to PC-SPES are different from those found when diethylstilbestrol (DES), a synthetic estrogen, is used, suggesting that the estrogenic moieties within PC-SPES do not drive this expression signature. In contrast, the expression profile of PC-CARE was almost identical to that of DES, highlighting that mixtures containing similar herbal compositions do not necessarily result in similar biological activities. Interestingly, these three agents cause similar in vitro morphological changes and growth effects on LNCaP. To validate the expression profiling data, we evaluated the protein expression and promoter activity of prostate-specific antigen (PSA), a gene induced by PC-SPES but repressed by DES. In order to gain a mechanistic understanding of how PC-SPES and DES affect PSA expression differently, LNCaP cells were transiently transfected with wild-type and mutagenized PSA promoter, ARE concatemers and appropriate controls. We provide evidence that androgen response elements (ARE) II and III within the promoter region are responsible for the suppressive effects of DES and stimulatory effects of PC-SPES. In addition, we show that the effects on PSA transcription are ARE specific in the case of DES while PC-SPES affects this promoter nonspecifically. In conclusion, expression profiling coupled with mechanistic target validation yield valuable clues as to the mode of action of complex botanical mixtures and provides a new way to compare objectively mixtures with similar components either for effect or quality assurance prior to their use in clinical trials.