Cancer Therapy

Biography

Biography: Dimple Chakravarty

Abstract

Sequencing of the human genome has revealed a myriad of insights into the complexities of transcriptional program and has shed light on regulatory role of the non-coding transcriptome beyond the speculated “transcriptional noise”. Long non coding RNAs (lncRNAs) comprise a heterogeneous group of non-coding transcripts (>200nt) that have emerged as key mediators of cellular homeostasis. We recently discovered the lncRNA NEAT1 and identified its role in prostate cancer (PCa) progression. NEAT1 expression is low in benign prostate cells but demonstrates a significant increase in expression with PCa progression. We provide experimental evidence to demonstrate that NEAT1 can drive oncogenic cascade via epigenetic modulation of chromatin. By RNA ISH on TMAs we have shown that NEAT1 is upregulated in both localized as well as metastatic prostate cancer compared to benign. Functionally, NEAT1 is a transcriptional regulator and RNAseq analysis identified a compendium of genes (NEAT1 signature) that are directly regulated by NEAT1. Analysis of a large clinical cohort suggested that NEAT1 is a novel prognostic biomarker of clinically aggressive disease and a predictive biomarker of patients with advanced prostate cancer. NEAT1 contributes to DNA damage and repair mechanisms and functions as a unique link between oncogenic signaling and DNA damage and response pathway. Biochemical studies reveal that NEAT1 is a histone chaperone and NEAT1 signaling converges at a yet undiscovered DDR pathway. Our studies also support the rationale that NEAT1 modulates large-scale chromatin reorganization for efficient repair of damaged loci. We have discovered a functional feed-back loop between genomic instability and cancer progression pathways that might also explain molecular basis for drug and radiation resistance observed in aggressive cancers. Specific targeting of NEAT1 using siRNA approach restores sensitivity to radiation in prostate cancer cells. Delineating the role of NEAT1 using a combined molecular-genome wide screen and analysis of NEAT1 in clinical samples will provide rationale for future NEAT1-targeted therapies. Acknowledgments/Funding: This work was supported by NCI R01 CA152057 (AS, MAR) and the Early Detection Research Network NCI U01 CA111275 (MAR), and the Prostate Cancer Foundation Young Investigator award (DC). Keywords: non coding RNA, Cancer progression, Epigenetic regulation, DNA damage and repair