Abstract
Alternative RNA splicing impacts the majority (>90%) of eukaryotic multi-exon genes, expanding the coding capacity and regulating the abundance of gene isoforms. Telomerase (hTERT) is a key example of a gene that is alternatively spliced during human fetal development and becomes dysregulated in nearly all cancers. Approximately 90% of human tumors use telomerase to synthesize de novo telomere repeats and obtain telomere-dependent cellular immortality. Paradigm shifting data indicates that hTERT alternative splicing, in addition to transcription, plays an important role in the regulation of active telomerase in cells. Our group and others are pursuing the basic science studies to progress this emerging area of telomerase biology. Recent evidence demonstrates that switching splicing of hTERT from the telomerase activity producing full-length hTERT isoform to alternatively spliced, non-coding isoforms may be a novel telomerase inhibition strategy to prevent cancer growth and survival. Thus, the goals of this review are to detail the general roles of telomerase in cancer development, explore the emerging regulatory mechanisms of alternative RNA splicing of the hTERT gene in various somatic and cancer cell types, define the known and potential roles of hTERT splice isoforms in cancer cell biology, and provide insight into new treatment strategies targeting hTERT in telomerase-positive cancers.
Highlights
40% of adults in the United States are expected to be diagnosed with cancer in their lifespan [1]
It is likely that potential trans-acting RNA-binding proteins, such as SRSF11 and hnRNPH2, compete for binding within important cis-elements to dictate a cell’s splicing fate. While these findings provide insight into potential therapeutic strategies to regulate hTERT splicing, and telomerase activity and telomere lengths, it is important to note that Listerman et al observed that overexpression of the -β variant protects breast cancer cells from apoptotic death [72]
We propose the use of a telomerase inhibitor as a cancer prevention strategy would only be indicated in populations with a genetic predisposition to cancer or a history of chronic exposure to cancer causing environmental stressors, by limiting the number of cells that develop immortality
Summary
40% of adults in the United States are expected to be diagnosed with cancer in their lifespan [1]. Only 1 in 1·107 human cells are thought to escape crisis and acquire the ability to maintain their very short telomeres necessary to achieve immortality that is characteristic of cancer [25] This indicates that telomere shortening and replicative senescence are potent blocks to cellular immortality and cancer progression. Overexpression of hTERT cDNA in telomerase negative cells has further been shown to prevent cellular senescence, increase telomerase activity, and stimulate the lengthening of telomeres in BJ fibroblasts [38,39] These findings strongly support the notion that hTERT is the rate-limiting, catalytic subunit necessary for telomerase enzyme activity, and that hTERT alone is sufficient to reconstitute cellular replication and immortality through telomerase activity and telomere length maintenance in most cells. This review will detail the emerging regulatory mechanisms of hTERT alternative RNA splicing and processing in various cell types, define the known and potential roles of hTERT splice isoforms in cancer cell biology, and provide mechanistic insights that may lead to new treatment strategies targeting the hTERT gene in telomerase positive cancers
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