TSPYL5 Depletion Induces Specific Death of ALT Cells through USP7-Dependent Proteasomal Degradation of POT1

Lee

et al. 2020

Preprint

Cancer stem cells (CSCs) are regarded as essential targets to overcome tumor progression and therapeutic resistance; however, practical targeting approaches are limited. Here, we identify testis-specific Y-like protein 5 (TSPYL5) as a CSC-associated factor that promotes stemness and epithelial-to-mesenchymal transition in therapy-resistant non-small cell lung cancer (NSCLC) cells. Aberrantly activated PI3K/AKT pathway in therapy-resistant NSCLC cells promotes TSPYL5 phosphorylation at threonine-120 (pT120), which inhibits ubiquitination and stabilizes TSPYL5. TSPYL5 pT120 also supports SUMOylation, which leads to its nuclear translocation and functions as a transcriptional repressor of PTEN. Nuclear TSPYL5 also activates the transcription of CSC-associated genes, ALDH1 and CD44. Collectively, TSPYL5 pT120 maintains persistent CSC-like characteristics via transcriptional activation of CSC-associated genes and via a positive-feedback loop between the AKT/TSPYL5/PTEN and PTEN/PI3K/AKT signaling pathways. However, inhibition of TSPYL5 pT120 can block aberrant AKT/TSPYL5/PTEN cyclic signaling and cancer stemness. Our study suggests TSPYL5 as a novel target for cancer therapy.

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting therapy-resistant lung cancer stem cells via disruption of the AKT/TSPYL5/PTEN positive-feedback loop

Lee

et al. 2020

Preprint

“…Targeting the ALT-specific telomere proteins may be another way to kill ALT + cells. TSPYL5 is a protein that is specifically expressed in ALT + cancer cells [104]. Interestingly, depletion of TSPYL5 induces USP7dependent proteasomal degradation of POT1, a component of the shelterin complex, leading to death of ALT + cells.…”

Section: Therapeutic Outlooksmentioning

confidence: 99%

Alternative lengthening of telomeres: from molecular mechanisms to therapeutic outlooks

2020

To escape replicative senescence, cancer cells have to overcome telomere attrition during DNA replication. Most of cancers rely on telomerase to extend and maintain telomeres, but 4-11% of cancers use a homologous recombination-based pathway called alternative lengthening of telomeres (ALT). ALT is prevalent in cancers from the mesenchymal origin and usually associates with poor clinical outcome. Given its critical role in protecting telomeres and genomic integrity in tumor cells, ALT is an Achilles heel of tumors and an attractive target for cancer therapy. Here, we review the recent progress in the mechanistic studies of ALT, and discuss the emerging therapeutic strategies to target ALT-positive cancers.

“…Other ALT-specific targets of interest include TSYPL5, a protein which inhibits the ubiquitin hydrolase USP7. TSYPL5 is a component of APBs that protects POT1 from poly-ubiquitination and subsequent proteosomal degradation [86]. However, it is not clear why TSYPL5 depletion and the associated degradation of POT1 was toxic to ALT cells only, while the viability of normal or telomerase positive cells was unchanged.…”

Section: Therapeutic Outlook and Challengesmentioning

confidence: 99%

ALT: A Multi-Faceted Phenomenon

Sommer

Royle

2020

Genes

One of the hallmarks of cancer cells is their indefinite replicative potential, made possible by the activation of a telomere maintenance mechanism (TMM). The majority of cancers reactivate the reverse transcriptase, telomerase, to maintain their telomere length but a minority (10% to 15%) utilize an alternative lengthening of telomeres (ALT) pathway. Here, we review the phenotypes and molecular markers specific to ALT, and investigate the significance of telomere mutations and sequence variation in ALT cell lines. We also look at the recent advancements in understanding the different mechanisms behind ALT telomere elongation and finally, the progress made in identifying potential ALT-targeted therapies, including those already in use for the treatment of both hematological and solid tumors.