BET Inhibitors Potentiate Chemotherapy and Killing of SPOP-Mutant Colon Cancer Cells via Induction of DR5.

Abstract

Bromodomain and extraterminal domain (BET) family proteins such as BRD4 are epigenetic readers that control expression of a number of oncogenic proteins. Targeting this family of proteins has recently emerged as a promising anticancer approach. BET inhibitors (BETi), either alone or in combination with other anticancer agents, have exhibited efficacy in a variety of tumors. However, the molecular mechanisms underlying differential response to BETi are not well understood. In this study, we report that death receptor 5 (DR5), a key component of the extrinsic apoptotic pathway, is markedly induced in response to BRD4 depletion and BETi treatment in colorectal cancer cells. Induction of DR5, following BET inhibition, was mediated by endoplasmic reticulum stress and CHOP-dependent transcriptional activation. Enhanced DR5 induction was necessary for the chemosensitization and apoptotic effects of BETi and was responsible for increased BETi sensitivity in colorectal cancer cells containing a mutation in speckle-type POZ protein (SPOP), a subunit of BRD4 E3 ubiquitin ligase. In a colorectal cancer xenograft model, BETi combined with chemotherapy suppressed the tumor growth in a DR5-dependent manner and potently inhibited patient-derived xenograft tumor growth with enhanced DR5 induction and apoptosis. These findings suggest that BETi alone or in combination with chemotherapy is effective against colorectal cancer due to enhanced DR5 induction and apoptosis. DR5 induction may also serve as a useful marker for designing personalized treatment and improved colorectal cancer combination therapies.Significance: These findings reveal how BET inhibition sensitizes chemotherapy and kills a subset of colon cancer cells with specific genetic alterations and may provide a new molecular marker for improving colon cancer therapies.

• Authors: Xiao Tan, Jingshan Tong, Yi-Jun Wang, Rochelle Fletcher, Robert E Schoen, Jian Yu, Liangfang Shen, Lin Zhang
• Journal: Cancer research (Cancer Res) Vol. 79 Issue 6 Pg. 1191-1203 (03 15 2019) ISSN: 1538-7445 [Electronic] United States
• PMID: 30674532 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• (+)-JQ1 compound
• Antimetabolites, Antineoplastic
• Azepines
• BRD4 protein, human
• Cell Cycle Proteins
• Nuclear Proteins
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Repressor Proteins
• SPOP protein, human
• TNFRSF10B protein, human
• Transcription Factors
• Triazoles
• Fluorouracil

Topics

• Animals
• Antimetabolites, Antineoplastic (pharmacology)
• Apoptosis
• Azepines (pharmacology)
• Cell Cycle Proteins (antagonists & inhibitors)
• Cell Proliferation
• Colonic Neoplasms (drug therapy, metabolism, pathology)
• Drug Synergism
• Female
• Fluorouracil (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Mutation
• Nuclear Proteins (genetics)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (genetics, metabolism)
• Repressor Proteins (genetics)
• Transcription Factors (antagonists & inhibitors)
• Triazoles (pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays