Antitelomerase Therapy Provokes ALT and Mitochondrial Adaptive Mechanisms in Cancer

Hu, Jian; Hwang, Soyoon; Liesa, Marc; Gan, Boyi; Sahin, Ergün; Jaskelioff, Mariela; Ding, Zhihu; Ying, Haoqiang; Boutin, Adam T.; Zhang, Hailei; Johnson, Shawn F.; Ivanova, Elena; Kost‐Alimova, Maria; Protopopov, Alexei; Wang, Yaoqi Alan; Shirihai, Orian S.; Chin, Lynda; DePinho, Ronald A.

doi:10.1016/j.cell.2011.12.028

Cited by 250 publications

(250 citation statements)

References 50 publications

(78 reference statements)

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“…In an effort to identify genetic events that may drive deactivation of terminal differentiation capacity, we surveyed The Cancer Genome Atlas (TCGA) GBM dataset for genes showing both recurrent copy number loss (GISTIC) (19,20) and possessing known roles in promoting nervous system development (ingenuity pathway analysis and PubMed). The ORFs of 71 genes that scored in both categories (SI Appendix, Table S1) were transduced individually into the GBM cell line LN319 and audited for anchorage-independent activity in the soft agar assay, which reflects both cell renewal and malignant potential.…”

Section: Resultsmentioning

confidence: 99%

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Neutralization of terminal differentiation in gliomagenesis

Yuan

et al. 2013

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

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An immature state of cellular differentiation-characterized by stem cell-like tendencies and impaired differentiation-is a hallmark of cancer. Using glioblastoma multiforme (GBM) as a model system, we sought to determine whether molecular determinants that drive cells toward terminal differentiation are also genetically targeted in carcinogenesis and whether neutralizing such genes also plays an active role to reinforce the impaired differentiation state and promote malignancy. To that end, we screened 71 genes with known roles in promoting nervous system development that also sustain copy number loss in GBM through antineoplastic assay and identified A2BP1 (ataxin 2 binding protein 1, Rbfox1), an RNAbinding and splicing regulator that is deleted in 10% of GBM cases. Integrated in silico analysis of GBM profiles to elucidate the A2BP1 pathway and its role in glioma identified myelin transcription factor 1-like (Myt1L) as a direct transcriptional regulator of A2BP1. Reintroduction of A2BP1 or Myt1L in GBM cell lines and glioma stem cells profoundly inhibited tumorigenesis in multiple assays, and conversely, shRNA-mediated knockdown of A2BP1 or Myt1L in premalignant neural stem cells compromised neuronal lineage differentiation and promoted orthotopic tumor formation. On the mechanistic level, with the top-represented downstream target TPM1 as an illustrative example, we demonstrated that, among its multiple functions, A2BP1 serves to regulate TPM1's alternative splicing to promote cytoskeletal organization and terminal differentiation and suppress malignancy. Thus, in addition to the activation of self-renewal pathways, the neutralization of genetic programs that drive cells toward terminal differentiation may also promote immature and highly plastic developmental states that contribute to the aggressive malignant properties of GBM.oncogenomics | cancer stem cells

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Section: Resultsmentioning

confidence: 99%

“…The GISTIC algorithm was described previously (19). Briefly, deleted genes were defined by genes residing in regions that are deleted in >5% of GBM samples and contain <50 genes.…”

Section: Methodsmentioning

confidence: 99%

Neutralization of terminal differentiation in gliomagenesis

Yuan

et al. 2013

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

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“…mtDNA damage caused by cellular senescence may contribute to the production of reactive oxygen species (ROS), resulting in telomere shortening (18). Past reviews have emphasized the importance of the telomere-p53-mitochondrion axis for cancer, suggesting that this may be targeted in future cancer therapy (19,20). Our recent studies (21,22) have also investigated these genetic changes in GC; however, their association has yet to be studied in cancer tissue samples.…”

Section: Introductionmentioning

confidence: 99%

Telomere length is correlated with mitochondrial DNA copy number in intestinal, but not diffuse, gastric cancer

et al. 2017

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Abstract.A positive correlation between telomere length and mitochondrial DNA (mtDNA) copy number has previously been observed in healthy individuals, and in patients with psychiatric disorders. In the present study, telomere length and mtDNA copy number were evaluated in gastric cancer (GC) tissue samples. DNA was extracted from 109 GC samples (including 82 intestinal, and 27 diffuse cases), and the telomere length and mtDNA copy number were analyzed using a quantitative-polymerase chain reaction assay. The relative telomere length and mtDNA copy number in tumor tissue, as compared with in normal tissue, (mean ± standard deviation) in all GC samples were 11.48±1.14 and 14.86±1.35, respectively. Telomere length and mtDNA copy number were not identified as exhibiting clinical or prognostic value for GC. However, positive correlations between telomere length and mitochondrial DNA copy number were identified in GC (r=0.408, P<0.001) and in the adjacent normal mucosa (r=0.363; P<0.001). When stratified by Lauren classification, the correlation was identified in intestinal type GC samples (r=0.461; P<0.001), but not in diffuse type GC samples (r= 0.225; P= 0.260). This result indicated that loss of the correlation of telomeres and mitochondrial function may induce the initiation or progression of GC pathogenesis.

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“…Indeed genetic or chemical inhibition of telomerase led to insurgence of ALT in cultured human cancer cells and mice. 10,11 Hence it is necessary to gain a thorough understanding of the molecular basis of the ALT pathway and to develop targeted anti-ALT therapies to be used alone or together with telomerase inhibitors.…”

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confidence: 99%