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BIOL-10. DISTRIBUTION AND VULNERABILITY OF TRANSCRIPTIONAL OUTPUTS ACROSS THE GENOME IN MYC-AMPLIFIED MEDULLOBLASTOMA CELLS

Publication ,  Conference
Yang, R; Wang, W; Dong, M; Roso, K; Bao, X; Pirozzi, C; Bigner, D; Yan, H; Ashley, D; Zhabotynsky, V; Zou, F; He, Y
Published in: Neuro-Oncology
June 1, 2021

Myc plays a central role in tumorigenesis by orchestrating the expression of genes essential to numerous cellular processes. While it is well established that Myc functions by binding to its target genes to regulate their transcription, the distribution of the transcriptional output across human genome in Myc-amplified cancer cells, and the susceptibility of such transcriptional outputs to therapeutic interferences remain to be fully elucidated. Here, we analyze the distribution of transcriptional outputs in Myc-amplified medulloblastoma (MB) cells by profiling nascent total RNAs within a temporal context. This profiling reveals a major portion of transcriptional action in these cells was directed at the genes fundamental to cellular infrastructures, including rRNAs and particularly those in the mitochondrial genome (mtDNA). Notably, even when Myc protein was depleted by as much as 80%, the impact on transcriptional outputs across the genome was limited, with notable reduction mostly in genes of involved in ribosomal biosynthesis, genes residing in mtDNA or encoding mitochondria-localized proteins, and those encoding histones. In contrast to the limited direct impact of Myc depletion, we found that the global transcriptional outputs were highly dependent on the activity of Inosine Monophosphate Dehydrogenases (IMPDHs), rate limiting enzymes for de novo guanine nucleotide synthesis and whose expression in tumor cells was positively correlated with Myc’s expression. Blockage of IMPDHs attenuated the global transcriptional outputs with a particularly strong inhibitory effect on the aforementioned infrastructure genes, which was accompanied by the abrogation of MB cell’s proliferation in vitro and in vivo. Together, our findings reveal a real time action of Myc as a transcriptional factor in tumor cells, gain new insight into the pathogenic mechanism underlying Myc-driven tumorigenesis, and support IMPDHs as a therapeutic vulnerability in MB cells empowered by a high level of Myc oncoprotein.

Duke Scholars

Published In

Neuro-Oncology

DOI

EISSN

1523-5866

ISSN

1522-8517

Publication Date

June 1, 2021

Volume

23

Issue

Supplement_1

Start / End Page

i5 / i5

Publisher

Oxford University Press (OUP)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 1112 Oncology and Carcinogenesis
  • 1109 Neurosciences
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Yang, R., Wang, W., Dong, M., Roso, K., Bao, X., Pirozzi, C., … He, Y. (2021). BIOL-10. DISTRIBUTION AND VULNERABILITY OF TRANSCRIPTIONAL OUTPUTS ACROSS THE GENOME IN MYC-AMPLIFIED MEDULLOBLASTOMA CELLS. In Neuro-Oncology (Vol. 23, pp. i5–i5). Oxford University Press (OUP). https://doi.org/10.1093/neuonc/noab090.017
Yang, Rui, Wenzhe Wang, Meichen Dong, Kristen Roso, Xuhui Bao, Christopher Pirozzi, Darell Bigner, et al. “BIOL-10. DISTRIBUTION AND VULNERABILITY OF TRANSCRIPTIONAL OUTPUTS ACROSS THE GENOME IN MYC-AMPLIFIED MEDULLOBLASTOMA CELLS.” In Neuro-Oncology, 23:i5–i5. Oxford University Press (OUP), 2021. https://doi.org/10.1093/neuonc/noab090.017.
Yang R, Wang W, Dong M, Roso K, Bao X, Pirozzi C, et al. BIOL-10. DISTRIBUTION AND VULNERABILITY OF TRANSCRIPTIONAL OUTPUTS ACROSS THE GENOME IN MYC-AMPLIFIED MEDULLOBLASTOMA CELLS. In: Neuro-Oncology. Oxford University Press (OUP); 2021. p. i5–i5.
Yang, Rui, et al. “BIOL-10. DISTRIBUTION AND VULNERABILITY OF TRANSCRIPTIONAL OUTPUTS ACROSS THE GENOME IN MYC-AMPLIFIED MEDULLOBLASTOMA CELLS.” Neuro-Oncology, vol. 23, no. Supplement_1, Oxford University Press (OUP), 2021, pp. i5–i5. Crossref, doi:10.1093/neuonc/noab090.017.
Yang R, Wang W, Dong M, Roso K, Bao X, Pirozzi C, Bigner D, Yan H, Ashley D, Zhabotynsky V, Zou F, He Y. BIOL-10. DISTRIBUTION AND VULNERABILITY OF TRANSCRIPTIONAL OUTPUTS ACROSS THE GENOME IN MYC-AMPLIFIED MEDULLOBLASTOMA CELLS. Neuro-Oncology. Oxford University Press (OUP); 2021. p. i5–i5.
Journal cover image

Published In

Neuro-Oncology

DOI

EISSN

1523-5866

ISSN

1522-8517

Publication Date

June 1, 2021

Volume

23

Issue

Supplement_1

Start / End Page

i5 / i5

Publisher

Oxford University Press (OUP)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 1112 Oncology and Carcinogenesis
  • 1109 Neurosciences