Assistant Professor

Research Areas
Telomerase Regulation in Cancer and Stem Cells

Research Interests

The lab focuses primarily on telomerase regulation. Unchecked, tumor cells divide unceasingly, and this is in large part why cancers are deadly. Most cancers rely on a common set of genes to support this indefinite growth; these genes code for the enzyme telomerase.

The TERT gene encodes the catalytic sub-unit of telomerase, which polymerizes telomeric DNA. This enzyme drives the indefinite proliferation of most cancer cells as well as normal stem cells (Greider and Blackburn 1989). TERT is transcriptionally silent in most adult cells and its expression is tightly regulated during cellular and organism development (Counter et al. 1992, Kim et al. 1994, Shay and Bachetti 1997).

The absence of telomerase in most cells is a major cause in mammalian aging. This leads to chromosome shortening, followed by cells ceasing their growth. Conversely, the continued expression of telomerase in stem cells and cancer cells allows them to counteract this deficiency and enables their indefinite cellular growth.

Mutations in genes for telomerase cause a wide spectrum of disorders including, premature aging syndromes. Studying telomerase regulation provides key insights into the mechanisms of these telomere diseases, as well as cancer and aging.

Please see our lab page for our research focus: https://sites.uab.edu/jstern/research-2/

For more information, please visit: https://sites.uab.edu/jstern/ .

Telomerase:

Telomerase was recently discovered to be aberrantly activated in cancer by mutations in the TERT proximal promoter (TPM) (Huang et al. 2013, Horn et al. 2013, Killela et al. 2013, Bell et al. 2015, Chiba et al 2015, Stern et al 2015). These heterozygous mutations drive monoallelic expression and are common in many cancer types, but are especially prevalent in glioblastomas, melanomas, myxoid liposarcomas, liver cancers, and bladder cancers. TPM associate with a distinct epigenetic state (Stern et al. 2017) and poorer patient survival in several cancer types (Rachakonda et al. 2013, Chan et al. 2015, George & Henderson et al. 2015, Simon et al. 2015, Lee, Barnhill et al. 2015, Bahrami et al. 2016, Nagore et al. 2016, Seynnaeve et al. 2017, Vuong et al. 2017) although the mechanisms driving these observations are unknown.

TPM tend to occur in slower growing cell types and are associated with older age at least in glioblastoma, thyroid cancer, and melanoma (4) suggesting that molecular features in certain cell types and older patients may drive the acquisition of these mutations.

Our recent work demonstrated that TPM cancers are a unique subset characterized by distinct gene and protein expression profiles dominated by epithelial-mesenchymal transition (EMT) markers and elevated RAS/BRAF/MAPK signaling. The basis for the association between TPM and these signatures is not well understood. While most cancers drive TERT expression without requiring these mutations, it appears in cells with mesenchymal features and elevated RAS pathway signaling, the acquisition of TERT promoter mutations provides a selective advantage.

EMT as a cancer therapeutic target There is compelling evidence that EMT promotes chemoresistance (Williams et al. 2019 Nature Rev Cancer). The EMT state in cancer is inherently transitory and is one of several different cancer traits that promote cellular plasticity. In EMT, clonal populations can display phenotypic heterogeneity, which when placed under therapeutic selection, facilitates the persistence of resistant cells that can eventually give rise to new populations. Much work is being done to find ways to target EMT in cancer including the application of combinatorial therapies, targeting pivotal nodes driving phenotypic switching, and reversing cellular plasticity. This includes specifically targeting transcription factors that promote EMT such as TWIST1, ZEB1 and SNAI1.

In glioblastoma, liver cancer, and bladder cancer cell lines, mutant TERT promoters recruit the housekeeping transcription factors GABPa & GABPb1 (Bell et al. 2015, Stern et al. 2015). Importantly, the long isoform, GABPb1L, regulates a restricted subset of genes, and in a mouse xenograft model of glioblastoma regulates expression from mutant TERT promoters (Mancini et al. 2018); in the absence of GABPb1L, mice largely failed to succumb to disease, demonstrating that telomerase was essential to cause fatalities in this well-established model of brain cancer.

Several recent studies reported that TERT mRNA expression in TPM cancers is supported by mitogen activated protein kinase (MAPK) signaling through the Ras pathway (Vallarelli et al. 2016, Li et al. 2016, Reyes-Uribe et al. 2018, Liu et al. 2018). It remains unknown whether there are additional common drivers across multiple cancer types that participate in this signaling pathway in TPM cancers.

The regulation of telomerase expression and function is now known to differ in many normal and pathogenic contexts. One broad aim of the lab is to elucidate the mechanisms governing telomerase function. In the course of pursuing this aim, our research has uncovered novel epigenetic relationships between DNA methylation and polycomb repressive complex 2 (PRC2)-mediated gene silencing operating in diseased and healthy contexts, specifically at the TERT locus, but also at other loci.

Epigenetics:

In addition to telomerase, the lab also studies how PRC2 and 5-methylcytosine (5mC) interact in vivo. Both PRC2 and 5mC are associated with gene silencing. Initial findings indicate their relationship is dysfunctional in cancer and aging.

PRC2 recruits to the TERT locus. This enzyme complex is responsible for tri-methylating lysine 27 of the histone 3 protein (H3K27me3). This epigenetic mark is strongly associated with gene silencing. PRC2-mediated gene silencing is essential during development to limit the expression of genes associated with later developmental stages. Along with H3K9me3 and DNA methylation on cytosines (5mC), PRC2 deposition of H3K27me3 is one of the major cellular components of epigenetic silencing. PRC2 activity is also dysregulated during aging.

PRC2 is a multi-subunit complex comprised of the obligate members EZH2, the catalytic subunit, as well as the scaffolding and recruitment partners EED and SUZ12. The enzyme complex typically has several additional, interchangeable protein partners that confer unique properties on the enzyme in vivo. These accessory proteins are mutually exclusive with one another in the complex and appear to define critical biological parameters, including recruitment to chromatin, where it contributes to regulation of gene expression. Previous studies suggest that PRC2 recruitment to chromatin is negatively regulated by the presence of 5mC in healthy cells. In contrast, our recent research has discovered that in cancer this relationship may be dysfunctional, including at the TERT locus. Thus, one aim of the lab is to understand this dysfunctional relationship.

Honors

• American Cancer Society Postdoctoral Fellowship 2016 – 2019
• CJ Martin Biomedical Postdoctoral Fellowship: 2013 – 2015
• Cancer Institute NSW Research Scholar Award, Ph.D. scholarship 2009 – 2012
• National Health & Biomedical Research Council Scholar Award, Ph.D. scholarship 2009 – 2012

Education

Graduate School
Ph.D., Children's Medical Research Institute, University of Sydney

Postdoctoral Fellowship
BioFrontiers Institute, University of Colorado, Boulder

Contact

Office
Kaul Human Genetics Building
Building Room 540D
720 20th Street South
Birmingham, AL 35294

Lab
Kaul Human Genetics Building
Building Room 566

Phone
(347) 975-9096

Email
jstern@uab.edu