Targeting MYC as a therapeutic intervention for anaplastic thyroid cancer.

Targeting MYC as a therapeutic intervention for anaplastic thyroid cancer.

J Clin Endocrinol Metab. 2017 Mar 28;:

Authors: Enomoto K, Zhu X, Park S, Zhao L, Zhu YJ, Willingham MC, Qi J, Copland JA, Meltzer P, Cheng SY

Abstract
Context: Recent studies showed that transcription of the MYC gene is driven by interaction of bromodomain and extraterminal domain (BET) proteins with acetylated histones on chromatin. A potent inhibitor, JQ1, which 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. It remains to be elucidated on the role of MYC in human ATC and whether JQ1 could effectively target MYC as a novel treatment modality.
Objective: To understand underlying molecular mechanisms of JQ1's effects on human ATC, we evaluated the efficacy of JQ1 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 4 ATC cell lines by suppression of MYC and elevation of p21and p27 to decrease phosphorylated Rb to 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 that the size and rate of tumor growth was inhibited by JQ1 via inhibition of p21-Cyclin/CDK-Rb-E2F signaling.
Conclusions: These results suggest targeting MYC protein could be a potential novel treatment modality for human ATC for which effective treatment options are limited.

PMID: 28368473 [PubMed - as supplied by publisher]

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