Targeting MYC as a therapeutic intervention for anaplastic thyroid cancer

Keisuke Enomoto, Xuguang Zhu, Sunmi Park, Li Zhao, Yuelin J. Zhu, Mark C. Willingham, Jun Qi, John A III Copland, Paul Meltzer, Sheue Yann Cheng

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Context: Recent studies showed that transcription of the MYC gene is driven by the interaction of bromodomain and extraterminal domain (BET) proteins with acetylated histones on chromatin. JQ1, a potent inhibitor that effectively disrupts the interaction of BET proteins with acetylated histones, preferentially suppresses transcription of the MYC gene. We recently reported that JQ1 decreased thyroid tumor growth and improved survival in a mouse model of anaplastic thyroid cancer (ATC) by targeting MYC transcription. The role of MYC in human ATC and whether JQ1 can effectively target MYC as a treatment modality have not been elucidated. Objective: To understand the underlying molecular mechanisms of JQ1, we evaluated its efficacy in human ATC cell lines and xenograft models. Design: We determined the effects of JQ1 on proliferation and invasion in cell lines and xenograft tumors. We identified key regulators critical for JQ1-affected proliferation and invasion of tumor cells. Results: JQ1 markedly inhibited proliferation of four ATC cell lines by suppression of MYC and elevation of p21and p27 to decrease phosphorylated Rb and delay cell cycle progression from the G0/G1 phase to the S phase. JQ1 blocked cell invasion by attenuating epithelial-mesenchymal transition signals. These cell-based studies were further confirmed in xenograft studies in which the size and rate of tumor growth were inhibited by JQ1 via inhibition of p21-cyclin/cyclin-dependent kinase-Rb-E2F signaling. Conclusions: These results suggest targeting of the MYC protein could be a potential treatment modality for human ATC for which effective treatment options are limited.

Original languageEnglish (US)
Pages (from-to)2268-2280
Number of pages13
JournalJournal of Clinical Endocrinology and Metabolism
Volume102
Issue number7
DOIs
StatePublished - Jul 1 2017

Fingerprint

Cells
Tumors
Transcription
Heterografts
Histones
Genes
Therapeutics
Cell Line
Neoplasms
Cell Cycle Resting Phase
Proteins
Cyclins
Epithelial-Mesenchymal Transition
Cyclin-Dependent Kinases
G1 Phase
Protein Transport
Growth
Tumor Cell Line
S Phase
Chromatin

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Enomoto, K., Zhu, X., Park, S., Zhao, L., Zhu, Y. J., Willingham, M. C., ... Cheng, S. Y. (2017). Targeting MYC as a therapeutic intervention for anaplastic thyroid cancer. Journal of Clinical Endocrinology and Metabolism, 102(7), 2268-2280. https://doi.org/10.1210/jc.2016-3771

Targeting MYC as a therapeutic intervention for anaplastic thyroid cancer. / Enomoto, Keisuke; Zhu, Xuguang; Park, Sunmi; Zhao, Li; Zhu, Yuelin J.; Willingham, Mark C.; Qi, Jun; Copland, John A III; Meltzer, Paul; Cheng, Sheue Yann.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 102, No. 7, 01.07.2017, p. 2268-2280.

Research output: Contribution to journalArticle

Enomoto, K, Zhu, X, Park, S, Zhao, L, Zhu, YJ, Willingham, MC, Qi, J, Copland, JAIII, Meltzer, P & Cheng, SY 2017, 'Targeting MYC as a therapeutic intervention for anaplastic thyroid cancer', Journal of Clinical Endocrinology and Metabolism, vol. 102, no. 7, pp. 2268-2280. https://doi.org/10.1210/jc.2016-3771
Enomoto, Keisuke ; Zhu, Xuguang ; Park, Sunmi ; Zhao, Li ; Zhu, Yuelin J. ; Willingham, Mark C. ; Qi, Jun ; Copland, John A III ; Meltzer, Paul ; Cheng, Sheue Yann. / Targeting MYC as a therapeutic intervention for anaplastic thyroid cancer. In: Journal of Clinical Endocrinology and Metabolism. 2017 ; Vol. 102, No. 7. pp. 2268-2280.
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