Balabhadrapatruni V. S. K. Chakravarthi

Production of paclitaxel by Fusarium solani isolated from Taxus celebica

A fungus was isolated from the stem cuttings of Taxus celebica, which produced paclitaxel in liquid-grown cultures. The fungus was identified as Fusarium solani based on colony characteristics, morphology of conidia and the 26S rDNA sequence. Paclitaxel was identified by chromatographic and spectroscopic comparison with authentic paclitaxel and its cytotoxic activity towards Jurkat cells in vitro.

UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses

Genomics data from The Cancer Genome Atlas (TCGA) project has led to the comprehensive molecular characterization of multiple cancer types. The large sample numbers in TCGA offer an excellent opportunity to address questions associated with tumo heterogeneity. Exploration of the data by cancer researchers and clinicians is imperative to unearth novel therapeutic/diagnostic biomarkers. Various computational tools have been developed to aid researchers in carrying out specific TCGA data analyses; however there is need for resources to facilitate the study of gene expression variations and survival associations across tumors. Here, we report UALCAN, an easy to use, interactive web-portal to perform to in-depth analyses of TCGA gene expression data. UALCAN uses TCGA level 3 RNA-seq and clinical data from 31 cancer types. The portals user-friendly features allow to perform: 1) analyze relative expression of a query gene(s) across tumor and normal samples, as well as in various tumor sub-groups based on individual cancer stages, tumor grade, race, body weight or other clinicopathologic features, 2) estimate the effect of gene expression level and clinicopathologic features on patient survival; and 3) identify the top over- and under-expressed (up and down-regulated) genes in individual cancer types. This resource serves as a platform for in silico validation of target genes and for identifying tumor sub-group specific candidate biomarkers. Thus, UALCAN web-portal could be extremely helpful in accelerating cancer research. UALCAN is publicly available at http://ualcan.path.uab.edu.

Development of Peptidomimetic Inhibitors of the ERG Gene Fusion Product in Prostate Cancer

Transcription factors play a key role in the development of diverse cancers, and therapeutically targeting them has remained a challenge. In prostate cancer, the gene encoding the transcription factor ERG is recurrently rearranged and plays a critical role in prostate oncogenesis. Here, we identified a series of peptides that interact specifically with the DNA binding domain of ERG. ERG inhibitory peptides (EIPs) and derived peptidomimetics bound ERG with high affinity and specificity, leading to proteolytic degradation of the ERG protein. The EIPs attenuated ERG-mediated transcription, chromatin recruitment, protein-protein interactions, cell invasion and proliferation, and tumor growth. Thus, peptidomimetic targeting of transcription factor fusion products may provide a promising therapeutic strategy for prostate cancer as well as other malignancies.

MicroRNA-101 regulated transcriptional modulator SUB1 plays a role in prostate cancer

MicroRNA-101, a tumor suppressor microRNA (miR), is often downregulated in cancer and is known to target multiple oncogenes. Some of the genes that are negatively regulated by miR-101 expression include histone methyltransferase EZH2 (enhancer of zeste homolog 2), COX2 (cyclooxygenase-2), POMP (proteasome maturation protein), CERS6, STMN1, MCL-1 and ROCK2, among others. In the present study, we show that miR-101 targets transcriptional coactivator SUB1 homolog (Saccharomyces cerevisiae)/PC4 (positive cofactor 4) and regulates its expression. SUB1 is known to have diverse role in vital cell processes such as DNA replication, repair and heterochromatinization. SUB1 is known to modulate transcription and acts as a mediator between the upstream activators and general transcription machinery. Expression profiling in several cancers revealed SUB1 overexpression, suggesting a potential role in tumorigenesis. However, detailed regulation and function of SUB1 has not been elucidated. In this study, we show elevated expression of SUB1 in aggressive prostate cancer. Knockdown of SUB1 in prostate cancer cells resulted in reduced cell proliferation, invasion and migration in vitro, and tumor growth and metastasis in vivo. Gene expression analyses coupled with chromatin immunoprecipitation revealed that SUB1 binds to the promoter regions of several oncogenes such as PLK1 (Polo-like kinase 1), C-MYC, serine-threonine kinase BUB1B and regulates their expression. Additionally, we observed SUB1 downregulated CDKN1B expression. PLK1 knockdown or use of PLK1 inhibitor can mitigate oncogenic function of SUB1 in benign prostate cancer cells. Thus, our study suggests that miR-101 loss results in increased SUB1 expression and subsequent activation of known oncogenes driving prostate cancer progression and metastasis. This study therefore demonstrates functional role of SUB1 in prostate cancer, and identifies its regulation and potential downstream therapeutic targets of SUB1 in prostate cancer.

Expression and Role of PAICS, a De Novo Purine Biosynthetic Gene in Prostate Cancer.

Our goal was to investigate de novo purine biosynthetic gene PAICS expression and evaluate its role in prostate cancer progression.

Erratum: Development of Peptidomimetic Inhibitors of the ERG Gene Fusion Product in Prostate Cancer (Cancer Cell (2017) 31(4) (532–548.e7)(S1535610817300600)(10.1016/j.ccell.2017.02.017))

Xiaoju Wang, Yuanyuan Qiao, Irfan A. Asangani, Bushra Ateeq, Anton Poliakov, Marcin Cie slik, Sethuramasundaram Pitchiaya, Balabhadrapatruni V.S.K. Chakravarthi, Xuhong Cao, Xiaojun Jing, Cynthia X. Wang, Ingrid J. Apel, Rui Wang, Jean Ching-Yi Tien, Kristin M. Juckette, Wei Yan, Hui Jiang, Shaomeng Wang, Sooryanarayana Varambally, and Arul M. Chinnaiyan* *Correspondence: arul@umich.edu http://dx.doi.org/10.1016/j.ccell.2017.05.001

miR-34a Regulates Expression of the Stathmin-1 Oncoprotein and Prostate Cancer Progression

In aggressive prostate cancers, the oncoprotein STMN1 (also known as stathmin 1 and oncoprotein 18) is often overexpressed. STMN1 is involved in various cellular processes, including cell proliferation, motility, and tumor metastasis. Here, it was found that the expression of STMN1 RNA and protein is elevated in metastatic prostate cancers. Knockdown of STMN1 resulted in reduced proliferation and invasion of cells and tumor growth and metastasis in vivo. Furthermore, miR-34a downregulated STMN1 by directly binding to its 3′-UTR. Overexpression of miR-34a in prostate cancer cells reduced proliferation and colony formation, suggesting that it is a tumor suppressor. The transcriptional corepressor C-terminal binding protein 1 (CtBP1) negatively regulated expression of miR-34a. Furthermore, gene expression profiling of STMN1-modulated prostate cancer cells revealed molecular alterations, including elevated expression of growth differentiation factor 15 (GDF15), which is involved in cancer progression and potentially in STMN1-mediated oncogenesis. Thus, in prostate cancer, CtBP1-regulated miR-34a modulates STMN1 expression and is involved in cancer progression through the CtBP1\miR-34a\STMN1\GDF15 axis. Implications: The CtBP1\miR-34a\STMN1\GDF15 axis is a potential therapeutic target for treatment of aggressive prostate cancer. Mol Cancer Res; 16(7); 1125–37. ©2017 AACR.

Abstract 5206: Role of CtBP1 as a transcriptional corepressor in prostate cancer.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: C-terminal Binding Protein 1 (CtBP1), a transcriptional co-repressor that regulates the expression of tumor suppressors and genes involved in cell death, is known to play a critical role in multiple cancers. Earlier, we showed that CtBP1 is overexpressed in metastatic prostate cancer. Furthermore, our studies indicated a role for CtBP1 in conferring radiation resistance to prostate cancer cell lines. We also demonstrated the functional role of CtBP1 in regulating prostate cancer cell growth in vitro and tumor growth and metastasis in vivo. Methods and Results: Our gene expression profiling and bioinformatics analysis found that multiple potential tumor suppressors are reactivated upon CtBP1 knockdown in multiple prostate cancer cell lines. We next validated these targets of CtBP1-mediated repression by qRTPCR and western blotting using CtBP1 stable knockdown prostate cancer cell lines, and in normal prostate epithelial PrEC cells overexpressing CtBP1. Our studies confirmed that CtBP1 targets multiple genes including SP8 transcription factor and kallikrein-related peptidase 10 (KLK10) among others. Knockdown of the reactivated gene led to a reversion of these cells to a more aggressive phenotype. Furthermore, our studies confirmed that the CtBP1 target genes are down-regulated in metastatic prostate cancer. Conclusion: Taken together, our studies demonstrated that dysregulated expression of CtBP1 plays an important role in prostate cancer progression by down-regulating the expression of multiple potential tumor suppressor genes. Thus, targeting CtBP1 in aggressive prostate cancer may have clinical significance. Citation Format: Balabhadrapatruni V. S. K. Chakravarthi, Satya Pathi, Heng Zheng, Javed Siddiqui, Lakshmi P. Kunju, Nallasivam Palanisamy, Sooryanarayana Varambally. Role of CtBP1 as a transcriptional corepressor in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5206. doi:10.1158/1538-7445.AM2013-5206

Targeting the link between late pregnancy and breast cancer.

Why does a first pregnancy after age 35 increase the risk of breast cancer, and what can be done to combat this?

Wnt receptor Frizzled 8 is a target of ERG in prostate cancer

Prostate cancer (PCa) is one of the most frequently diagnosed cancers among men. Many molecular changes have been detailed during PCa progression. The gene encoding the transcription factor ERG shows recurrent rearrangement, resulting in the overexpression of ERG in the majority of prostate cancers. Overexpression of ERG plays a critical role in prostate oncogenesis and development of metastatic disease. Among the downstream effectors of ERG, Frizzled family member FZD4 has been shown to be a target of ERG. Frizzled‐8 (FZD8) has been shown to be involved in PCa bone metastasis. In the present study, we show that the expression of FZD8 is directly correlated with ERG expression in PCa. Furthermore, we show that ERG directly targets and activates FZD8 by binding to its promoter. This activation is specific to ETS transcription factor ERG and not ETV1. We propose that ERG overexpression in PCa leads to induction of Frizzled family member FZD8, which is known to activate the Wnt pathway. Taken together, these findings uncover a novel mechanism for PCa metastasis, and indicate that FZD8 may represent a potential therapeutic target for PCa.