Telomere Maintenance-Associated PML Is a Potential Specific Therapeutic Target of Human Colorectal Cancer

Gong, Peng; Wang, Hua; Zhang, Jingsong; Fu, Yudong; Zhu, Zhengmao; Wang, Jinmiao; Yin, Yu; Wang, Haiying; Zhou, Zhongli; Yang, Jiao; Liu, Linlin; Gou, Mo; Zeng, Ming; Yuan, Jinghua; Wang, Rui; Pan, Xinghua; Xiang, Rong; Weissman, Sherman M.; Qi, Feng; Liu, Lin

doi:10.1016/j.tranon.2019.05.010

Cited by 8 publications

(7 citation statements)

References 84 publications

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“…PML depletion induces telomere damage, nuclear and chromosomal abnormalities, and senescence [ 32 ]. It is commonly found in tumors with telomere shortening and high proliferation, which suggests its critical role in telomere maintenance and cell viability [ 33 ]. In our analysis, higher PML expression in the Short TL group than in the Long TL group was observed in five cancer types (STAD, THYM, hepatocellular carcinoma (LIHC), LGG, and cholangiocarcinoma (CHOL)) ( Figure 2 b), suggesting that PML expression level is a marker for telomere length in these cancer types.…”

Section: Resultsmentioning

confidence: 99%

Pan-Cancer Analysis of Alternative Lengthening of Telomere Activity

Sung

Lim

Joung

et al. 2020

Cancers

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Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism that extends telomeres in cancer cells. It influences tumorigenesis and patient survival. Despite the clinical significance of ALT in tumors, the manner in which ALT is activated and influences prognostic outcomes in distinct cancer types is unclear. In this work, we profiled distinct telomere maintenance mechanisms (TMMs) using 8953 transcriptomes of 31 different cancer types from The Cancer Genome Atlas (TCGA). Our results demonstrated that approximately 29% of cancer types display high ALT activity with low telomerase activity in the telomere-lengthening group. Among the distinct ALT mechanisms, homologous recombination was frequently observed in sarcoma, adrenocortical carcinoma, and kidney chromophobe. Five cancer types showed a significant difference in survival in the presence of high ALT activity. Sarcoma patients with elevated ALT had unfavorable risks (p < 0.038) coupled with a high expression of TOP2A, suggesting this as a potential drug target. On the contrary, glioblastoma patients had favorable risks (p < 0.02), and showed low levels of antigen-presenting cells. Together, our analyses highlight cancer type-dependent TMM activities and ALT-associated genes as potential therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

Pan-Cancer Analysis of Alternative Lengthening of Telomere Activity

Sung

Lim

Joung

et al. 2020

Cancers

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“…), or against the protein TSYPL5, a recently identified protein critical for ALT positive cells viability ( 226 ), could potentially provide additional therapeutic strategies for treating ALT tumors. Physiological relevance of this approach was confirmed in colorectal cancer (CRC) tissues with short telomeres, correlating with increased PML levels, APB formation and proliferation rate ( 227 ). Inhibition of ATR in patient-derived colorectal cancer organoids reduced APB formation, shortened telomeres and reduced proliferation ( 227 ).…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 97%

“…Physiological relevance of this approach was confirmed in colorectal cancer (CRC) tissues with short telomeres, correlating with increased PML levels, APB formation and proliferation rate ( 227 ). Inhibition of ATR in patient-derived colorectal cancer organoids reduced APB formation, shortened telomeres and reduced proliferation ( 227 ).…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 97%

PML nuclear bodies and chromatin dynamics: catch me if you can!

Corpet

Kleijwegt

Roubille

et al. 2020

Nucleic Acids Research

127

146

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Eukaryotic cells compartmentalize their internal milieu in order to achieve specific reactions in time and space. This organization in distinct compartments is essential to allow subcellular processing of regulatory signals and generate specific cellular responses. In the nucleus, genetic information is packaged in the form of chromatin, an organized and repeated nucleoprotein structure that is a source of epigenetic information. In addition, cells organize the distribution of macromolecules via various membrane-less nuclear organelles, which have gathered considerable attention in the last few years. The macromolecular multiprotein complexes known as Promyelocytic Leukemia Nuclear Bodies (PML NBs) are an archetype for nuclear membrane-less organelles. Chromatin interactions with nuclear bodies are important to regulate genome function. In this review, we will focus on the dynamic interplay between PML NBs and chromatin. We report how the structure and formation of PML NBs, which may involve phase separation mechanisms, might impact their functions in the regulation of chromatin dynamics. In particular, we will discuss how PML NBs participate in the chromatinization of viral genomes, as well as in the control of specific cellular chromatin assembly pathways which govern physiological mechanisms such as senescence or telomere maintenance.

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“…Various strategies are being developed to target the TMMs, telomerase reviewed by [ 128 ] and ALT [ 140 , 141 , 142 , 143 ]. The apparently complex relationship between POT1 mutations and oncogenesis makes POT1 a difficult treatment target at present.…”

Section: Clinical Implications Of Pot1 Alterations In Cancermentioning

confidence: 99%

Role of POT1 in Human Cancer

Poulos

Reddel

2020

Cancers

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Telomere abnormalities facilitate cancer development by contributing to genomic instability and cellular immortalization. The Protection of Telomeres 1 (POT1) protein is an essential subunit of the shelterin telomere binding complex. It directly binds to single-stranded telomeric DNA, protecting chromosomal ends from an inappropriate DNA damage response, and plays a role in telomere length regulation. Alterations of POT1 have been detected in a range of cancers. Here, we review the biological functions of POT1, the prevalence of POT1 germline and somatic mutations across cancer predisposition syndromes and tumor types, and the dysregulation of POT1 expression in cancers. We propose a framework for understanding how POT1 abnormalities may contribute to oncogenesis in different cell types. Finally, we summarize the clinical implications of POT1 alterations in the germline and in cancer, and possible approaches for the development of targeted cancer therapies.

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Telomere Maintenance-Associated PML Is a Potential Specific Therapeutic Target of Human Colorectal Cancer

Cited by 8 publications

References 84 publications

Pan-Cancer Analysis of Alternative Lengthening of Telomere Activity

Pan-Cancer Analysis of Alternative Lengthening of Telomere Activity

PML nuclear bodies and chromatin dynamics: catch me if you can!

Role of POT1 in Human Cancer

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