Abhishek A. Chakraborty, Ph.D.
Center for GU Malignancies Research
Lerner Research Institute,
9500 Euclid Avenue, Cleveland, Ohio 44195
Our laboratory studies chromatin biology in the context of dysregulated activity of oxygen-dependent enzymes (or dioxygenase), such as the JumonjiC-family histone demethylases (or KDMs). The physiological implications of dioxygenase dysfunction is relevant in kidney cancer, where these enzymes are often mutated; and also more broadly in the context of hypoxic tumors, where these enzymes can be inactivated due to inadequate oxygen availability. Our laboratory’s central theme is to exploit dioxygenase dysfunction—and the resulting epigenetic anomalies—to identify targetable vulnerabilities in the context of cancer.
To address these goals, our laboratory is currently focused on three major questions:
1.) Defining the Relevance of the EZH1 histone methyltransferase as a Target in Kidney Cancer. Our previous work showed that the EZH1 histone methyltransferase counteracts the deleterious effects of KDM dysfunction in kidney cancer. Using a diverse array of genetic and pharmacological tools, in combination with genomics and metabolomics analyses, we are now studying the mechanisms of this EZH1 dependency. In collaboration with the kidney cancer clinicians at Cleveland Clinic, we hope to ultimately explore the feasibility of targeting EZH1 for kidney cancer therapy.
2.) Defining the Contribution of Dioxygenases in Cell State and Differentiation. Recently we described that certain KDMs, such as KDM6A, act as cellular “Oxygen Sensors”. By responding to changes in physiological oxygen, the "oxygen sensors" act as molecular switches that profoundly influence cellular response to hypoxia. We are now investigating the biological consequences of hypoxia-dependent inactivation of these enzymes in human cancer. By developing novel high-throughput genetic and chemical screening strategies, our laboratory hopes to define actionable therapeutic interventions that can redress the biological consequences of KDM loss in human pathologies.
3.) Exploiting Dioxygenase Dysfunction to Identify Super-enhancer Linked Genetic Dependencies. We previously identified specific histone modification signatures in kidney cancer [e.g. accumulation of Histone H3 modified by acetylation at Lysine 27 (H3K27ac)]. H3K27ac routinely decorates certain enhancer-dense regulatory clusters, called super-enhancers, which typically mark critical genes that regulate cellular identity and/or tumorigenic state. Consistent with this theme, we have identified numerous super-enhancer linked targets in kidney cancer. In ongoing work we are employing metabolomics analysis, genetic screens, and pharmacological tools to define super-enhancer linked dependencies in kidney cancer. In time, we hope that one or more of these candidates could become prospects for therapeutic targeting.
How do we sense and respond to a lack of adequate oxygen and why does it matter? While we all know the physiological responses (think gasping or panting) typically associated with insufficient oxygen availability; our cells are equally hardwired at a molecular level to respond to this adversity. We do so by employing a uniquely evolved set of proteins that function only in the presence of oxygen. Loss of oxygen switches off these proteins and in the process triggers a slew of downstream consequences, including changes in the levels of numerous genes and metabolites. Together, these changes allow oxygen-deficient cells to adapt and survive in the face of what would otherwise be a catastrophic event. Unfortunately, what were processes that we originally evolved for survival, are also hijacked by cancer cells, especially as they become more aggressive and outgrow their oxygen supply. We propose that studying these molecular responses could reveal the central schemes that oxygen-deprived cancer cells employ for survival. Blocking these processes in cancer cells, in turn, could prove lethal - and exploited for therapeutic purposes. Our laboratory, therefore, studies the proteins and processes involved in sensing and responding to oxygen loss, with the hope that this knowledge can ultimately identify creative ways to disarm what is a hostile takeover.
- Chakraborty AA, Laukka T, Myllykoski M, Ringel AE, Booker MA, Tolstorukov MY, Meng Y, Meier S, Jennings RB, Creech AL, Herbert ZT, Spinelli J, McBrayer SK, Olenchock BA, Jaffe JD, Haigis MC, Beroukhim R, Signoretti S, Koivunen P, and Kaelin WG, Jr. (2019) The UTX Tumor Suppressor Directly Senses Oxygen to Control Chromatin and Cell Fate, Science, 363: 1217-1222.
- Oser MG, Fonseca R, Chakraborty AA, Brough R, Spektor A, Gulati A, Buss E, McBrayer SK, Cowley GS, Novak JS, Nguyen QD, Brulle-Soumare L, Taylor P, Cairo S, Signoretti S, Ryan CJ, Pease EJ, Maratea K, Pellman D, Ashton S, Lord CJ, Barry ST, and Kaelin WG, Jr. (2019) Cells Lacking the RB1 Tumor Suppressor Gene are Hyperdependent on Aurora B Kinase for Survival, Cancer Discovery, 9: 230-247.
- McBrayer SK, Mayers JR, DiNatale GJ, Shi DD, Khanal J, Chakraborty AA, Sarosiek KA, Briggs KJ, Robbins AK, Sewastianik T, Shareef SJ, Olenchock BA, Parker SJ, Tateishi K, Spinelli JB, Islam M, Haigis MC, Looper RE, Ligon KL, Bernstein BE, Carrasco RD, Cahill DP, Asara JM, Metallo CM, Yennawar NH, Vander Heiden MG, Kaelin WG Jr. (2018) Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma, Cell, 175: 101-116.
- Chakraborty AA, Nakamura E, Qi J, Creech A, Jaffe JD, Paulk J, Nagulapalli K, McBrayer SK, Cowley GS, Pineda J, Song J, Wang YE, Carr SA, Root DE, Signoretti S, Bradner JE, and Kaelin WG, Jr. (2017), HIF Activation Causes Synthetic Lethality Between the VHL Tumor Suppressor and the EZH1 Histone Methyltransferase, Sci Transl Med., 9: pii: eaal5272.
- Guo J, Chakraborty AA, Liu P, Gan W, Zheng X, Cheng JQ, Toker A, Asara JM, Zhang Q, Kaelin WG, Jr., and Wei W (2016), pVHL suppresses Akt kinase activity and oncogenic function in a proline-hydroxylation dependent manner, Science, 353: 929-32.
- Cho H, Du X, Rizzi JP, Liberzon E, Chakraborty AA, Gao W, Carvo I, Signoretti S, Bruick R, Josey JA, Wallace EM, and Kaelin WG, Jr. (2016), On-Target Efficacy of a HIF2α Antagonist in Preclinical Kidney Cancer Models, Nature, 539: 107-11.
For a Complete Publication List, see:
Dr. Chakraborty will study one candidate oncogene’s contributions to kidney cancer, looking specifically at the role it may play in cancer cell metabolism, thanks to a new award from the Department of Defense, his first federal research grant.