Gerald V. Denis, PhD

Denis_head_shot

Gerald V. Denis, Ph.D.

Title: Associate Professor of Pharmacology and Medicine; Flow Cytometry Core Facility
Education: A. B. Harvard College; M. Sc. University of Tokyo; Ph. D. University of California, Berkeley

Research interests: The overall goal of my lab is to understand the fundamental mechanisms of transcriptional control of growth and development, and particularly, how chromatin-based disruptions of the eukaryotic cell cycle can lead to malignancy. We focus on the BET bromodomains proteins, a family comprised of BRD2 (originally named RING3), BRD3 and BRD4 in somatic cells, which are important as transcriptional co-regulators. I was the first to report a function for a BET protein, and to link these co-regulators to human cancer. The BET protein field has grown from sixteen papers, when I first published my work, to over 1,300 to date; they have since been implicated in several cancer types. Our recent data have established that BET proteins provide a functional link between obesity, inflammation and breast cancer progression in post-menopausal women. We are presently investigating the role of the BET proteins in the non-tumor cells of the breast cancer microenvironment, which are important for chemoresistance and metastasis.

Medical significance: New small molecules such as JQ1 inhibit the BET bromodomain proteins, demonstrating that chromatin is ‘druggable’ and raising excitement that new, epigenetically-acting drugs with anti-inflammatory properties could also have impact for breast cancer patients. However, fundamental biology in this area is underdeveloped; current clinical trials are premature and possibly dangerous. My novel work has highlighted the need for deeper mechanistic understanding of tractable cancers, the undesirable side effects of current pan-BET inhibitors because BRD2 and BRD4 functionally oppose each other, and the urgent need for new, next generation drugs.

Clinical interests: B cell leukemia and lymphoma. Breast cancer, especially among women with co-morbid obesity and diabetes. Transcriptional regulation of inflammation and metabolism in the tumor microenvironment of both breast and prostate cancers.

Research summary of work in cancer. We developed a transgenic mouse model for B cell non-Hodgkin’s lymphoma (NHL) with constitutive B lineage expression of BRD2. This co-regulator functions at least in part through a chromatin-dependent pathway that targets the gene cyclin A and promotes S phase events. Brd2 complexes recruit E2Fs and histone H4-directed histone acetyltransferase to the cyclin A promoter, contributing to cell cycle control in B cells. In transgenic mice, constitutive Brd2 expression destabilizes the cell cycle, leading to NHL-like malignancy and peripheral leukemia.

However, we reported that Brd2‑hypomorphic mice surprisingly show low-inflammatory, ‘metabolically protected’ obesity. Gene disruption of the Brd2 locus was accomplished by lacZ insertion into the promoter region of the gene, creating apparent haploinsufficiency, allowing these mice to be viable. The resultant low-inflammatory characteris­tics of Brd2 lo mice include uncoupling of Toll-like recep­tor and TNF signaling from NF-κB-directed transcription of diverse pro-inflammatory cytokine genes. The mouse phenotype provides a model for a population of obese humans for whom obesity is not entirely unhealthy.

These ‘metabolically healthy’ obese human subjects comprise about 25% of the adult obese population in the United States, and preserve insulin sensitivity and glucose tolerance. These insights have major importance for our understanding of the molecular mechanisms that couple obesity and chronic inflammation to cancer. We went on to show for the first time that such humans have about half the risk for colon, post-menopausal breast and endometrial cancer of obese humans with metabolic disease.

Relevant recent original research

  1. Andrieu G, Denis GV. BET proteins exhibit transcriptional and functional opposition in the epithelial-to-mesenchymal transition. Molecular Cancer Research. February 7, 2018. DOI:10.1158/1541-7786.MCR-17-0568 PMCID: pending
  2. Palmer JR, Castro-Webb N, Bertrand K, Bethea TN, Denis GV. Type 2 diabetes and incidence of estrogen receptor negative breast cancer in African American women. Cancer Research 2017; 77: 6462-69. PMID: 29141994
  3. Denis GV, Sebastiani P, Andrieu G, Tran AH, Strissel KJ, Lombardi FL, Palmer JR. Relationships among obesity, Type 2 diabetes and plasma cytokines in African American women. Obesity (Silver Spring) 2017; 25: 1916-1920. PMCID: PMC5669048
  4. Charlot M, Castro-Webb N, Bethea TN, Bertrand K, Boggs DA, Denis GV, Adams-Campbell LL, Rosenberg L, Palmer JR. Diabetes and breast cancer mortality in Black women. Cancer Causes Control 2017; 28: 61-67. PMCID: PMC5528173
  5. Andrieu G, Tran AH, Strissel KJ, Denis GV. BRD4 regulates breast cancer dissemination through Jagged1/Notch1 signaling. Cancer Research 2016;76:6555–67. PMCID: PMC5290198

 Research summary of work in immune cell proliferation, inflammation and HIV transcriptional repression. BET proteins co-activate NF-κB-regulated genes that encode pro-inflammatory cytokines. Inhibition or knockdown of BET proteins confers potent anti-inflammatory benefits to obese/inflamed or septic animals, and protects obese animals from insulin resistance and glucose intolerance. Thus, these factors are potentially important targets for Type 2 diabetes, a chronic inflammatory disease. Yet we also discovered that inhibition of BRD4 upregulates HIV transcription in latently infected human T cells, which highlights an important safety problem with current clinical trials of JQ1 for cancer. My lab continues to investigate these mechanisms.

Relevant recent original research

  1. DeFuria J, Belkina AC, Jagannathan-Bogdan M, Snyder-Cappione J, Carr JD, Nersesova Y, Markham D, Strissel KJ, Watkins A, Allen J, Bouchard J, Toraldo G, Jasuja R, Obin MS, McDonnell ME, Apovian C, Denis GV, Nikolajczyk BS. B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile. Proc Natl Acad Sci USA 2013;110:5133–8. PMCID: PMC3612635
  2. Banerjee C, Archin N, Michaels D, Belkina AC, Denis GV, Bradner J, Sebastiani P, Margolis DM, Montano M. BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leuk Biol 2012;92:1147–54. PMCID: PMC3501896
  3. Belkina AC, Nikolajczyk BS, Denis GV. BET protein function is required for inflammation: Brd2 genetic disruption and BET inhibitor JQ1 impair mouse macrophage inflammatory responses. J Immunol 2013;190: 3670–8. PMCID: PMC 3608815
  4. Belkina AC, Blanton WP, Nikolajczyk BS, Denis GV. The double bromodomain protein Brd2 promotes B cell expansion and mitogenesis. J Leuk Biol 2014;95:451-60. PMCID: PMC3923082

Relevant recent reviews

  1. ‘Obesity-associated’ breast cancer in lean women: Metabolism and inflammation as critical modifiers of risk. Denis GV, Palmer JR. Cancer Prevention Research 2017; 10:267-269. PMID: 28408379 PMCID: PMC5500903
  2. Nicholas DA, Andrieu G, Strissel KJ, Nikolajczyk BS, Denis GV. BET bromodomain proteins and epigenetic regulation of inflammation: Implications for type 2 diabetes and breast cancer. Cellular and Molecular Life Sciences 2017; 74:231-243. PMID: 27491296 DOI:1007/s00018-016-2320-0
  3. Andrieu G, Belkina AC, Denis GV. Clinical trials for BET inhibitors run ahead of the science. Drug Discovery Today 2016. http://dx.doi.org/10.1016/j.ddtec.2016.06.004. PMCID: PMC5116321
  4. Strissel KJ, Denis GV, Nikolajczyk BS. Immune regulators of inflammation in obesity-associated type 2 diabetes and coronary artery disease. Current Opinion in Endocrinology, Diabetes and Obesity 2014;21:330-8. PMID: 25106001 PMCID: PMC425195
  5. Denis GV, Hamilton JA. Healthy obese persons: How can they be identified and do metabolic profiles stratify risk? Current Opinion in Endocrinology, Diabetes and Obesity 2013;20:369–76. PMID 23974763
  6. Denis GV, Obin MS. (2012). ‘Metabolically healthy obesity’: Origins and implications. Molecular Aspects of Medicine http://dx.doi.org/10.1016/j.mam.2012.10.004 PMID: 23068072. PMCID: PMC3583231