Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER

Newberg

Proc. Natl. Acad. Sci. U.S.A.

et al. 2016

Epithelial-mesenchymal transition (EMT) is thought to contribute to metastasis and chemoresistance in patients with hepatocellular carcinoma (HCC), leading to their poor prognosis. The genes driving EMT in HCC are not yet fully understood, however. Here, we show that mobilization of Sleeping Beauty (SB) transposons in immortalized mouse hepatoblasts induces mesenchymal liver tumors on transplantation to nude mice. These tumors show significant down-regulation of epithelial markers, along with up-regulation of mesenchymal markers and EMT-related transcription factors (EMTTFs). Sequencing of transposon insertion sites from tumors identified 233 candidate cancer genes (CCGs) that were enriched for genes and cellular processes driving EMT. Subsequent trunk driver analysis identified 23 CCGs that are predicted to function early in tumorigenesis and whose mutation or alteration in patients with HCC is correlated with poor patient survival. Validation of the top trunk drivers identified in the screen, including MET (MET proto-oncogene, receptor tyrosine kinase), GRB2-associated binding protein 1 (GAB1), HECT, UBA, and WWE domain containing 1 (HUWE1), lysine-specific demethylase 6A (KDM6A), and protein-tyrosine phosphatase, nonreceptor-type 12 (PTPN12), showed that deregulation of these genes activates an EMT program in human HCC cells that enhances tumor cell migration. Finally, deregulation of these genes in human HCC was found to confer sorafenib resistance through apoptotic tolerance and reduced proliferation, consistent with recent studies showing that EMT contributes to the chemoresistance of tumor cells. Our unique cell-based transposon mutagenesis screen appears to be an excellent resource for discovering genes involved in EMT in human HCC and potentially for identifying new drug targets.H CC is the sixth most common cancer and the third-leading cause of cancer-related deaths worldwide (1). In the United States, the incidence of HCC is increasing, and overall 5-y survival is now <12%, despite recent progress in diagnostic and therapeutic modalities (2). This high mortality rate is related mainly to a high recurrence rate and associated intrahepatic or extrahepatic metastases (1). Patients with HCC who develop metastasis are no longer eligible for liver transplantation therapy and have very limited therapeutic options. Currently, sorafenib is the sole systemic antineoplastic agent for HCC described in the National Comprehensive Cancer Network (NCCN) guideline (3); however, its clinical benefit is limited (4), and alternative effective treatments are needed for these patients.Epithelial-mesenchymal transition (EMT) is a complex differentiation process whereby epithelial cells lose their identity and acquire mesenchymal characteristics (5). EMT is observed routinely in developmental processes, but is also believed to play an important role in the migration, invasion, and metastasis of various cancers (6-9). It also promotes the generation of cancer stem cells, thereby contributing to tumor recurrence and metastasis...

Section: Discussionmentioning

confidence: 99%

Section: Identification Of Ccgs Driving the Development Of Mesenchymalmentioning

confidence: 99%

Transposon mutagenesis identifies genes and cellular processes driving epithelial-mesenchymal transition in hepatocellular carcinoma

Newberg

Proc. Natl. Acad. Sci. U.S.A.

et al. 2016

Israel Journal of Chemistry

“…Targeting processes involved in epigenetic regulation of gene expression has also been investigated. Inhibition of the H3 K27me3 demethylases KDM6 A/B by GSKÀJ4 was shown to promote EMT in MCF-7 and HMLER cells, [74] suggesting that targeting epigenetic modifiers could provide the means to alter EMT for therapeutic purposes. Diallyl trisulfide (DAST) targets FOXQ1, [75] a protein implicated in embryonic development, cell cycle regulation, tissue-specific gene expression, cell signaling, and tumorigenesis in MCF-7 and SUM159 cells.…”

Section: Miscellaneousmentioning

confidence: 99%

Targeting Cancer Stem Cells with Small Molecules

Müller

Cañeque

Acevedo

et al. 2017

Cancers arise as a result of physiological imbalances and subsequent uncontrolled cell division. Cancer initiation requires a set of biochemical alterations, including some occurring at the genetic and epigenetic levels. Thus, tumors are heterogeneous in nature making it challenging to selectively target different cancer cells by means of small molecule intervention. The paradigm of cancer stem cells (CSCs) describes subpopulations of cells with high selfrenewal and tumor-seeding capacity. These cells, typically refractory to conventional therapies, can give rise to relapse after treatment. Combinatorial strategies, including drugs that selectively target this population of cells, have emerged in recent years. Here, we review how discovery-basedunbiased -screening approaches [1] have helped identify small molecules that specifically target CSCs. We also highlight biological pathways characteristic of CSCs that can potentially be selectively targeted in a hypothesis-driven manner by small molecules. We describe molecules that effectively target CSCs and emphasize what is known about their biological modes of action. The diversity and complexity of biochemical processes that CSCs may be addicted to, raises the question of how selective targeting of these pathways can be achieved. This challenge may be addressed by the continuing production of structurally complex and diverse small molecules using target and diversity-oriented synthesis approaches.[2]

“…For example, the formation of heterochromatin requires Dicer expression. 40,41 Additionally, siRNA mediated knockdown of Dicer induced histone acetylation and promoted heterochromatin switching to euchromatin. 40 Hypoxia, through the inhibition of H3K27me3 demethylases KDM6A/B, was able to epigenetically silence the DICER promoter and reduce Dicer expression in breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

The epigenetic regulation of Dicer and microRNA biogenesis by Panobinostat

2017

microRNAs (miRs) are small noncoding RNAs that regulate/fine tune many cellular protein networks by targeting mRNAs for either degradation or translational inhibition. Dicer, a type III endoribonuclease, is a critical component in miR biogenesis and is required for mature microRNA production. Abnormal Dicer expression occurs in numerous cancer types and correlates with poor patient prognosis. Recent reports have demonstrated that epigenetic agents, including histone deacetylase inhibitors (HDACi), may regulate Dicer and miR expression. HDACi are a class of epigenetic agents used to treat cancer, viral infections, and inflammatory disorders. However, little is known regarding the epigenetic regulation of miR biogenesis and function. We therefore investigated whether clinically successful HDACi modulated Dicer expression and found that Panobinostat, a clinically approved HDACi, enhanced Dicer expression via posttranscriptional mechanisms. Studies using proteasome inhibitors suggested that Panobinostat regulated the proteasomal degradation of Dicer. Further studies demonstrated that Panobinostat, despite increasing Dicer protein expression, decreased Dicer activity. This suggests that Dicer protein levels do not necessarily correlate with Dicer activity and mature miR levels. Taken together, we present evidence here that Panobinostat posttranscriptionally regulates Dicer/miR biogenesis and suggest Dicer as a potential therapeutic target in cancer.