Current Research

1. Transcriptional and epigenetic regulation of cancer metabolic reprogramming

How metabolic reprogramming is initiated and maintained in cancer cells is a central question of cancer research. We have pioneered the concept that histone lysine methyltransferases and demethylases are key players in reprogramming cell metabolism for cancer cell growth and proliferation. Therefore, they represent a new class of metabolic oncogenes or tumor suppressors and new drug targets for cancer therapy. We are currently investigating how oncogenic transcription factors, such as MYCN and ATF4, cooperate with epigenetic regulators, such as enzymes that modify histones and RNA, in transcriptional and translational reprogramming of cancer metabolism. We study metabolic pathways that generate building blocks for the synthesis of proteins, lipids, and nucleic acids. We are also testing small molecule inhibitors and drugs that block key metabolic pathways as cancer therapeutics in cell lines and animal models of human cancer.

Representative Citations:

  • Ding, J., Li, T., Wang, X., Zhao, E., Choi, J., Yang, L., Zha, Y., Dong, Z., Huang, S., Asara, J.M., Cui, H., Ding, H.-F. The histone H3 methyltransferase G9A epigenetically activates the serine-glycine synthesis pathway to sustain cancer cell survival and proliferation. Cell Metabolism. 18:896-907. 2013. PMID: 24315373; PMCID: PMC3878056
  • Zhao, E., Ding, J., Xia, Y., Liu, M., Ye, B., Choi, J., Yan, C., Dong, Z., Huang, S., Zha, Y., Yang, L., Cui, H., and Ding, H.-F.  KDM4C and ATF4 cooperate in transcriptional control of amino acid metabolism. Cell Rep. 14:506-519, 2016. PMID: 26774480; PMCID: PMC4731315
  • Liu, M., Xia, Y., Ding, J., Ye, B., Zhao, E., Choi, J.-H., Alptekin, A., Yan, C., Dong, Z., Huang, S., Yang, L., Cui, H., Zha, Y., and Ding, H.-F. Transcriptional profiling reveals a common metabolic program in high-risk human neuroblastoma and mouse neuroblastoma sphere-forming cells. Cell Rep. 17:609-623, 2016. PMID: 27705805; PMCID: PMC5536348
  • Xia Y., Ye B., Ding J., Yu Y., Alptekin A., Thangaraju, M., Prasad, D. P., Ding Z.-C., Park E., Choi J., Gao B., Fiehn O., Yan C., Dong Z., Zha Y., Ding H.-F.  Metabolic reprogramming by MYCN confers dependence on the serine-glycine-one-carbon biosynthetic pathway. Cancer Res. 79:3837–50, 2019. PMID: 31088832; PMCID: PMC6679782
  • Alptekin A., Ye B., Yu Y., Poole C.J., van Riggelen J., Zha Y., Ding H.-F. Glycine decarboxylase is a transcriptional target of MYCN required for neuroblastoma cell proliferation and tumorigenicity. Oncogene, DOI: 10.1038/s41388-019-0967-3, 2019. PMID: 31444411; PMCID PMC6908766
  • Li X., Cai L., Zhang M., Yu X., Chen X., Zhang J. Ding H.-F., Yan C. ATF3 Promotes the Serine Synthesis Pathway and Tumor Growth under Dietary Serine Restriction. Cell Rep. 36:109706, 2021. PMID: 34551291 PMCID: PMC8491098

2. Neuroblastoma biology and therapy

A major area of our research is the biology of neuroblastoma, a common pediatric cancer of the sympathetic nervous system. Our work has revealed new mechanisms for the oncogenic activity of MYCN in neuroblastoma pathogenesis by regulation of cell proliferation and apoptosis and by promoting the expansion of a population of PHOX2B+ neuronal progenitor cells. Importantly, we identified PHOX2B as a specific marker for neuroblastoma, with potential applications in diagnosis and prognosis.

Representative Citations:

  • Cui, H., Hu, B., Li, T., Ma, J., Alam, G., Gunning, W.T., and Ding, H.-F.  Bmi-1 is required for the tumorigenicity of neuroblastoma cells. Am. J. Pathol. 170:1370-1378. 2007. PMCID: PMC1829469
  • Alam, G., Cui, H., Shi, H., Ding, J., Lin, M., Maltese, W., and Ding, H.-F.  MYCN promotes the expansion of Phox2B-positive neuronal progenitors to drive neuroblastoma development. Am. J. Pathol. 175:856-866. 2009. PMID: 19608868; PMCID: PMC2716980
  • Mao, L., Ding, J., Zha, Y., Yang, L., King, W., Cui, H., and Ding, H.-F.  HOXC9 links cell cycle exit and neuronal differentiation and is a prognostic marker in neuroblastoma. Cancer Res. 71:4314-4324. 2011. PMID: 21507931; PMCID: PMC3116998
  • Mao, L., Ding, J., Perdue, A., Yang, L., Zha, Y., Ren, M., Huang, S., Cui, H., and Ding, H.-F.  Cyclin E1 is a common target of BMI1 and MYCN and a prognostic marker for neuroblastoma progression. Oncogene 31:3785-3795. 2012.
  • Calao, M., Sekyere, E.O., Cui, H.J., Cheung, B.B., Thomas, W.D., Keating, J.B, Raif, A., Jankowski, K., Davies, N.P., Bekkum, M.V., Chen, B., Tan, O., Ellis, T., Norris, M.D., Haber, M., Kim, E.S., Shohet, J.M., Trahair, T.N., Liu, T., Wainwright, B.J., Ding, H. F., and Marshall, G.M.  Direct effects of Bmi1 on p53 protein stability inactivate oncoprotein stress responses in embryonal cancer precursor cells at tumor initiation. Oncogene 32:3616-3626. 2013. PMID: 22907436
  • Yu Y., Ding J., Zhu S., Alptekin A., Dong Z., Yan C., Zha Y., Ding H.-F. Therapeutic targeting of both dihydroorotate dehydrogenase and nucleoside transport in MYCN-amplified neuroblastoma. Cell Death Dis 12:821, 2021. PMID: 34462431; PMCID: PMC8405683
  • Olsen, T.K., Dyberg, C., Embaie B., Alchahin A., Milosevic J., Ding J., Otte J., Tümmler C., Myrberg I.H., Westerhout E.M., Koster J., Versteeg R., Ding H.-F., Kogner P., Johnsen J.-I., Sykes D.B., Baryawno N. DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma. JCI Insight 7:153836. 2022. PMID: 35943801

3. Molecular and metabolic basis of stress-induced cell death

In collaboration with other investigators, our work has provided new insights into stress-induced metabolic reprogramming and the pathogenic role of stress-induced cell death.

Representative Citations:

  • Cui, H., Guo, M., Xu, D., Ding, Z.-C., Zhou, G., Ding, H.-F., Tang, Y., Yan, C. The stress-responsive gene ATF3 activates ATM signaling by regulating the histone acetyltransferase Tip60. Nature Comm. 5: 6752, 2015. PMCID: PMC4407828
  • Livingston, M.J., Ding, H.-F., Huang, S., Hill, J.A., Dong, Z. Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction. Autophagy. 12:976-998, 2016. PMCID: PMC4922446
  • Wang S., Liu A., Wu G., Ding H.-F., Huang S., Nahman S., Dong Z. The CPLANE protein Intu protects kidneys from ischemia-reperfusion injury by targeting STAT1 for degradation. Nature Comm. 9:1234, 2018. PMCID: PMC5964315
  • Ma Z., Li L., Livingston M., Mi Q-S., Zhang M., Ding H.-F., Huo Y., Mei C., and Dong Z. p53/microRNA-214/ULK1 axis impairs renal tubular autophagy in diabetic kidney disease. J Clin Invest 130:5011-5026, 2020. PMID: 32804155; PMCID: PMC7456229
  • Wang L., Liu Y., Du T., Yang H., Lei L., Guo M., Ding H-F., Zhang J., Wang H., Chen X., Yan C. ATF3 promotes erastin-induced ferroptosis by suppressing system Xc–. Cell Death Diff. 27:662-675, 2020. PMID: 31273299; PMCID: PMC7206049
  • Lu C., Yang D., Klement J.D., Colson Y.L., Oberlies N.H., Pearce C.J., Colby A.H., Grinstaff M.W., Ding H.-F., Shi H., Liu, K. G6PD functions as a metabolic checkpoint to regulate granzyme B expression in tumor-specific cytotoxic T lymphocytes. J ImmunoTher Cancer. 10:e003543. 2022
  • Lu C., Yang,D., Klemen J., Colson Y., Oberlies N., Pearce C., Colby A., Grinstaff M., Liu Z., Shi H., Ding H.-F., Liu K. H3K9me3 represses G6PD expression to suppress pentose phosphate pathway and ROS production to promote human mesothelioma growth. Oncogene. 41:2651-2662, 2022