Howard Hall, BRB 9009
Education and Training
Graduate Study: I obtained my PhD from Women’s and Children’s Hospital, University of Adelaide, Australia. My graduate training was completed under the guidance of Drs. Grant Sutherland and Dr. David Callen.
Postdoctoral training: My initial postdoctoral research was focused on understanding the role of genetic variations in human diseases, primarily intellectual disabilities, schizophrenia and hypertension. At this point in my research career it was clear to me that although genetic variations have huge impact on the etiology of diseases, great heterogeneity in complex disorders meant that the cellular environment as a whole should be explored for better disease management. I wanted to combine my expertise in the genetics of disease with molecular, biochemical, and systems approaches to complex diseases. Therefore, I chose to work with Dr. Girnun at the University of Maryland, as it afforded me the opportunity to extend my research training in metabolic pathways altered in complex phenotypes.
Tumor, Cancer, cancer metabolism
Bhalla, K, Hwang, B., Dewi, R., Choi, J-H., Dewi, R., Ou, L., Twaddell, W., Mclenithan, J., Voronkov, M., Stock, M., Perez, E., Stock, J., Pozharskiy, E., Girnun, G.D. N-Acetyl Farnesyl Cysteine is a novel class of PPARγ ligand with partial and full agonist activity in vitro and in vivo. J. Biol Chem. 286: 41626-416335, 2011. PMID: 21979952
Bhalla, K, Hwang, B., Dewi, R., Twaddell, W., Olga G. Goloubeva, Kwok-Kin Wong, Neeraj K. Saxena, Shyam Biswal and Girnun, G.D. Metformin prevents hepatocellular carcinoma by antagonizing hepatic lipogenesis. Cancer Prev Res April 2012 5:544-552 PMID: 22467080.
Bhalla, K., Hwang, B.J., Dewi, R., Twaddell, W. Frang, H.B., Vafai, S.B., Vazquez, F.,Puigserver, P., Boros, L.G. Girnun, G.D. The metabolic coactivator PGC1α promotes tumor growth by coordinating a gene expression program driving de novo fatty acid synthesis. Cancer Res. 71:6888-6889, 2011. PMID:21914785
Vazquez F, Lim JH, Chim H, Bhalla K, Girnun G, Pierce K, Clish CB, Granter SR, Widlund HR, Spiegelman BM, Puigserver P. PGC1α expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell. 23(3):287-301, 2013.
Bhalla, K*., Wan-ju, Liu., Naseri, E., Hwang, B., Thompson Keyata, Vafai, S., Anders, L., Sicinski, P., Girnun, G.D. Inhibition of PGC1α by cyclin D1/CDK4 mediates a switch from oxidative metabolism. Diabetes. 2014 Oct;63(10):3266-78. PMID:24947365 *Commentary on the article by Sofianos Andrikopoulos: The Proliferative Gene Cyclin D1 and Gluconeogenesis—Could Suppressing Glucose Production Also Promote Cancer? Diabetes 2014;63:3177-3179; doi:10.2337/db14-0857
Montal ED, Dewi R, Bhalla K, Ou L, Hwang BJ, Ropell AE, Gordon C, Liu WJ, DeBerardinis RJ, Sudderth J, Twaddel W, Boros LG, Shroyer KR, Duraisamy S, Drapkin R, Powers RS, Rohde JM, Boxer MB, Wong KK, Girnun GD. PEPCK coordinates the regulation of central carbon metabolism to promote cancer cell growth. Molecular Cell. 2015 Nov 19;60(4):571-83. PMID:26481663
Bhalla K, Eyre HJ, Whitmore SA, Sutherland GR, Callen DF. C16orf5, a novel proline-rich gene at 16p13.3, is highly expressed in the brain. J Hum Genet. 1999;44(6):383-7. PubMed PMID: 10570909.
Bhalla K, Luo Y, Buchan T, Beachem MA, Guzauskas GF, Ladd S, Bratcher SJ, Schroer RJ, Balsamo J, DuPont BR, Lilien J, Srivastava AK. Alterations in CDH15 and KIRREL3 in patients with mild to severe intellectual disability. Am J Hum Genet. 2008 Dec;83(6):703-13. doi: 10.1016/j.ajhg.2008.10.020. Epub 2008 Nov 13. PubMed PMID: 19012874; PubMed Central PMCID: PMC2668064.
Bhalla K, Phillips HA, Crawford J, McKenzie OL, Mulley JC, Eyre H, Gardner AE, Kremmidiotis G, Callen DF. The de novo chromosome 16 translocations of two patients with abnormal phenotypes (mental retardation and epilepsy) disrupt the A2BP1 gene. J Hum Genet. 2004;49(6):308-11. Epub 2004 May 18. PubMed PMID: 15148587.
Prasad MK, Bhalla K, Pan ZH, O'Connell JR, Weder AB, Chakravarti A, Tian B, Chang YP. A polymorphic 3'UTR element in ATP1B1 regulates alternative polyadenylation and is associated with blood pressure. PLoS One. 2013 Oct 1;8(10):e76290. doi: 10.1371/journal.pone.0076290. eCollection 2013. PubMed PMID: 24098465; PubMed Central PMCID: PMC3788127.
Callen DF, Eyre H, McDonnell S, Schuffenhauer S, Bhalla K. A complex rearrangement involving simultaneous translocation and inversion is associated with a change in chromatin compaction. Chromosoma. 2002 Sep;111(3):170-5. Epub 2002 Aug 6. PubMed PMID: 12355206.
Tumor microenvironment plays an important role in development of cancer. My current research is focused on cancer metabolism. In the long term I would like to understand contribution of cellular metabolism in the manifestation of complex disorders like cancer, diabetes and congenital diseases.
Identification of a novel PPARy ligand, acetyl farnesyl cysteine (AFC). Obesity is one of the prominent components of the metabolic syndrome and is the number one risk factor for diabetes. Currently approved drugs for the treatment of diabetes include TZDs such as pioglitazone and rosiglitazone. However, despite their widespread use concerns exist regarding the safety. We identified N-acetyl farnesyl cysteine (AFC) as a novel PPARyligand. AFC activated several PPARγ target genes as effectively as rosiglitazone (Angptl4, Adrp, and AdipoQ), but was a partial agonist of aP2, a PPARytarget gene associated with adiposity. We also examined if AFC is present endogenously given the presence of its farnesyl moiety. We observed AFC in both serum and tissues of humans and rodents. Since the liver appeared to have higher levels of AFC than other tissues we compared endogenous AFC levels from livers of lean versus obese mice. Following 20 weeks on a high fat diet, AFC was present at about 5 ng/mL in the livers of lean control C57Bl/6J mice. Remarkably, AFC was not detected in the livers of obese mice. This is the first example of an endogenous PPARyligand that shows altered levels in a pathological setting. Importantly, treatment of diabetic mice with AFC restored glucose homeostasis to a similar degree as rosiglitazone but without the weight gain typically observed with rosiglitazone.
Metformin prevents liver carcinogenesis by decreasing lipogenesis. Although a number of preclinical studies suggested anticancer properties of metformin in a number of tissues, none directly examined its effect on preventing carcinogenesis in the liver, one of its main sites of action. We directly showed for the first time that metformin prevents liver carcinogenesis by inhibiting lipogenesis.. The study garnered media attention and was published in Cancer Prevention Research with Cover Article and Featured Perspective, Cancer Prev Res. 5:500- 502, 2012. Interestingly, metformin did not increase AMPK activation, often shown to be a metformin target. Rather it inhibited various lipogeinc genes. Therefore unlike inhibitors of fatty acid synthesis that target only one step, our data demonstrates that metformin regulates multiple pathways involved in fatty acid synthesis. Thus, metformin will be sensitive to patients with other disorders associated with hepatic carcinoma like fatty liver disease (NAFLD) in which increased lipid synthesis is observed.
The transcriptional coactivator PGC1α promotes angiogenesis during tumor growth. Angiogenesis enables cancer cells to keep up with the intense metabolic demands of the tumor. PGC1α promotes tumor growth by induction of angiogenic gene program.
Impact of hypoxia on Diffuse large B cell lymphoma (DLBCL). Diffuse large B cell lymphoma (DLBCL) is a B cell derived lymphoid malignancy affecting 30% to 35% of lymphoma patients. It is clinically a very aggressive tumor subtype, genetically heterogeneous, and complex in nature. Conventional therapies cure only 50% of the patient population. Because of tumor heterogeneity and complexity it is difficult to treat refractory cases with currently available regimens. Therefore novel strategies are urgently required to improve patient survival. Thus, a thorough understanding of how hypoxic environment coordinately regulates various cellular processes in lymphoma is crucial to better target the tumor environment. This will facilitate developing novel metabolic therapies for treatment of lymphoma.
ATM regulates expression of Foxo3a and mitochondrial function in response to DNA damage in diffuse large B-cell lymphoma. Patients with Ataxia-telangiectasia (AT), a neurological disorder that occurs due deletion or mutation in Ataxia-telangiectasia mutated (ATM) gene, have a propensity to develop lymphoma. Cells lacking ATM, a kinase critical to the cellular DNA damage response (DDR), have an attenuated DDR to DNA double strand breaks. Previous reports and published data from our lab indicate that ATM affects the association of HuR binding protein with target mRNAs, including FOXO3a and SIRT1. These molecules regulate important cellular processes, including DNA repair and mitochondrial metabolism. The project is focused to study how ATM exerts its effect on lymphoma development in response to DNA damage by regulating FOXO3a and SIRT1.
Mid-Atlantic Nutrition Obesity Research Center (NORC) Pilot and feasibility grant, 2012: "The role of AFC in linking inflammation and type II diabetes”. Role: PI Research goal: To determine if AFC exerts its enhanced anti-inflammatory effects by promoting M2 macrophages, which improve adipocyte metabolism and glucose homeostasis.