Co-inhibition of BET proteins and NF-κB as a potential therapy for colorectal cancer through synergistic inhibiting MYC and FOXM1 expressions

Cell Death & Disease
Tingyu WuLong Cui

Abstract

The bromodomain and extra-terminal domain inhibitors (BETi) are promising epigenetic drugs for the treatment of various cancers through suppression of oncogenic transcription factors. However, only a subset of colorectal cancer (CRC) cells response to BETi. We investigate additional agents that could be combined with BETi to overcome this obstacle. JQ1-resistant CRC cells were used for screening of the effective combination therapies with JQ1. RNA-seq was performed to explore the mechanism of synergistic effect. The efficacy of combinational treatment was tested in the CRC cell line- and patient-derived xenograft (PDX) models. In BETi-sensitive CRC cells, JQ1 also impaired tumor angiogenesis through the c-myc/miR-17-92/CTGF+THBS1 axis. CTGF knockdown moderately counteracted anti-angiogenic effect of JQ1 and led to partially attenuated tumor regression. JQ1 decreased c-myc expression and NF-κB activity in BETi-sensitive CRC cells but not in resistant cells. Bortezomib synergistically sensitized BETi-resistant cells to the JQ1 treatment, and JQ1+Bortezomib induced G2/M arrest in CRC cells. Mechanistically, inhibition of NF-κB by Bortezomib or NF-κB inhibitor or IKK1/2 siRNA all rendered BETi-resistant cells more sensitive to BETi...Continue Reading

References

Apr 1, 1987·Cancer·K SikoraJ Watson
Jun 12, 1997·Oncogene·W W MarhinL Z Penn
Mar 31, 1999·Proceedings of the National Academy of Sciences of the United States of America·X W WangC C Harris
Aug 30, 2000·Proceedings of the National Academy of Sciences of the United States of America·D W FelsherJ M Bishop
Jul 24, 2001·Medical and Pediatric Oncology·Y Tsuchida, P Therasse
Oct 9, 2002·Genes & Development·Troy A BaudinoJohn L Cleveland
Sep 9, 2004·Proceedings of the National Academy of Sciences of the United States of America·Luiz F ZerbiniJin-Rhong Zhou
Feb 4, 2005·Nature Cell Biology·Robert H Costa
Aug 3, 2005·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Helen MackayAmit Oza
Jul 11, 2006·Nature Clinical Practice. Oncology·Tommaso CaravitaMario Boccadoro
Aug 1, 2006·Nature Genetics·Michael DewsAndrei Thomas-Tikhonenko
Mar 23, 2007·Nature·Owen J SansomAlan R Clarke
Dec 24, 2008·Molecular and Cellular Biology·Bo HuangLin-Feng Chen
Sep 6, 2011·Cell·Jake E DelmoreConstantine S Mitsiades
Apr 3, 2012·Cell·Chi V Dang
Jul 20, 2012·Nature·UNKNOWN Cancer Genome Atlas Network
Mar 22, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Nikhil C Munshi, Kenneth C Anderson
Mar 30, 2013·Science·Bert VogelsteinKenneth W Kinzler
Aug 24, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Giuseppe BaroneLouis Chesler
Nov 13, 2014·Nature Communications·Michael V GormallyShankar Balasubramanian
Aug 18, 2018·The Oncologist·Yvette L KasamonRichard Pazdur

❮ Previous
Next ❯

Citations

Aug 31, 2020·European Journal of Pharmacology·Wanjing DingGuangming Mei
Nov 2, 2019·Gene·Atena SoleimaniSeyed Mahdi Hassanian
Dec 4, 2020·International Journal of Molecular Sciences·Sara El-Sahli, Lisheng Wang
Jan 14, 2020·Pharmacology & Therapeutics·Oliver Bechter, Patrick Schöffski
May 1, 2021·Cancers·Lukas JohnMarc-Steffen Raab
May 25, 2021·Frontiers in Oncology·Fangyuan LiuPeng Du

❮ Previous
Next ❯

Methods Mentioned

BETA
xenograft
xenografts
RNA-seq
transfection
flow cytometry

Software Mentioned

Calcusyn
Deseq2

Related Concepts

Related Feeds

Angiogenesis Inhibitors to Treat Cancer

Cancer treatments including angiogenesis inhibitors prevent tumor cells from receiving nutrients and oxygen. Here is the latest research on angiogenesis inhibitors for the treatment of cancer.

Cancer Epigenetics and Senescence (Keystone)

Epigenetic changes are present and dysregulated in many cancers, including DNA methylation, non-coding RNA segments and post-translational protein modifications. The epigenetic changes may be involved in regulating senescence in cancer cells. This feed captures the latest research on cancer epigenetics and senescence.

Cancer Epigenetics & Metabolism (Keystone)

Epigenetic changes are present and dysregulated in many cancers, including DNA methylation, non-coding RNA segments and post-translational protein modifications. The epigenetic changes may or may not provide advantages for the cancer cells. This feed focuses on the relationship between cell metabolism, epigenetics and tumor differentiation.