Epigenetic Mechanisms of Gene Expression in Thoracic Malignancies

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Novel in-vitro models and correlative experiments with primary tumor/normal tissue specimens have been utilized to identify epigenomic alterations which contribute to initiation and progression of lung and esophageal cancers and malignant pleural mesotheliomas. A steady stream of manuscripts have been published by our group describing the epigenomic effects of cigarette smoke and other environmental carcinogens in normal aerodigestive tract epithelial cells and thoracic cancer cells in-vitro and in-vivo. Recently, a series of comprehensive experiments were conducted to examine the epigenenomic and transcriptomic effects of hookah smoke relative to conventional cigarette smoke in normal and immortalized human respiratory epithelial cells. CSC and WPC mediated distinct as well as overlapping transcriptome signatures, and pathway modulations that were cell line and dose-dependent. Epiregulin (EREG) encoding a master regulator of EGFR signaling which has been implicated in progression of lung cancers and maintenance of cancer stem cells was up-regulated, whereas Filamin A Interacting Protein 1-Like (FILIP1L) and API-3 binding protein (ABI3BP) encoding putative mediators of senescence were down-regulated in the five cell lines following CSC and WPC exposures. In collaboration with Dr. Steven Libutti we have extended these studies demonstrating that methylation of FILIP1L is a common event in human lung adenocarcinogenesis which is linked to inflammation and production of immunosuppressive mucins. This manuscript has been tentatively accepted for publication. In additional studies we have demonstrated the cigarette smoke enhances esophageal carcinogenesis by disrupting a repressive feedback look between miR-145 and the pro-metastatic chromatin binding protein LOXL2. Briefly cigarette smoke up-regulates LOXL2 which increases LOXL2 occupancy within the miR-143 host gene that encodes miR143 and miR 145. Repression of the miR-143 HG reduces interaction of miR-145 with the LOXL2 transcript promoting growth and invasion of esophageal adenocarcinoma cells in-vitro and in-vivo. A manuscript pertaining to these studies is tentatively accepted for publication pending revisions. Additional efforts have focused on delineation of epigenetic mechanisms contributing to malignant pleural mesotheliomas (MPM), and identification of novel therapeutic targets in these neoplasms. These studies led to our demonstration that ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1)- a master regulator of DNA methylation is us upregulated in MPM. Short term asbestos exposure induced UHRF1 expression in normal mesothelial cells. Knockdown of UHRF1 down-regulated DNMT1, and reversed global DNA hypomethylation, inhibiting proliferation, invasion, and clonogenicity of MPM cells, as well as growth of MPM xenografts. These effects were phenocopied by exposure of MPM cells/xenografts to HDM2 inhibitors currently in clinical development. Additional efforts have been devoted to examining the prevalence and natural history of mesotheliomas arising in patients with BAP1 tumor predisposition syndrome (TPDS). A unique protocol evaluating the use of photon counting CT imaging, liquid biopsies, and minimally invasive surveillance has been initiated in our Branch. We have identified a number of subclinical malignancies in these patients. Two intervention protocols using targeted epigenetic agents are being finalized for scientific and IRB review. The protocols will determine if oral DNA demethylating agents and HDM2 inhibitors that target epigenetic drivers in mesotheliomas can prevent progression of subclinical disease to life threatening mesotheliomas. These protocols are expected to open in the next 4-6 months.