Picture1.jpg

Figure 1. The cause and consequence of chromatin abnormality in cancer: Schematic illustration of pathways to arrive at an aberrant chromatin state in cancer cells. Upper panel shows oncohistone “K-to-M” mutations dominantly sequester and inhibit the corresponding histone methyltransferases (HMT), resulting in globally decreased histone methylation. Lower panel shows the oncometabolite 2-hydroxyglutarate (2HG) produced by cancer-associated isocitrate dehydrogenase (IDH1/2) mutations competitively inhibits α-ketoglutarate (αKG)-dependent TET family DNA hydroxylases and histone demethylases (KDM), leading to accumulation of DNA and histone methylation. These pathways act to promote oncogenesis through blockade of cellular differentiation and expansion of hyper-proliferative progenitor cells, a mechanism distinct from that of classic oncogenes and tumor suppressor genes. Suc, succinate; 5mc, 5-methylcytosine; 5hmc, 5-hydroxymethylcytosine.

 

Oncohistones: elucidating the oncogenic mechanisms of histone H3 mutations

Specific missense mutations in the histone H3 genes were found in the majority of pediatric brainstem gliomas and chondroblastomas. The highly clustered mutational patterns and only 1 of the 32 alleles encoding human histone H3 being mutated imply that the mutations are dominant or neomorphic, yet the underlying oncogenic mechanism has been unclear. As a postdoctoral fellow in the laboratory of Dr. C. David Allis, I demonstrated that the H3K36M/I mutations inhibit the activity of H3K36 methyltransferases and reprogram the genome-wide landscape of histone lysine methylation, resulting in altered gene expression, impaired mesenchymal differentiation and development of sarcoma. Furthermore, novel H3K36M mutations, together with mutually exclusive loss-of-function mutations in the H3K36 methyltransferase NSD1, define a molecularly distinct and clinically aggressive subtype of head and neck squamous cell carcinomas. These studies provide a unifying molecular mechanism underlying several human cancers driven by the so-called "oncohistones".

 

Oncometabolites: connecting altered cell metabolism to chromatin abnormality in cancer

Hotspot mutations in the metabolic enzymes isocitrate dehydrogenase 1 (IDH1) and IDH2 are frequently identified in patients with intermediate-grade gliomas, acute myeloid leukemias, chondrosarcomas and cholangiocarcinomas. IDH1/2 mutations were shown to result in the abnormal production of 2-hydroxyglutarate (2HG), but the function of the so-called "oncometabolite" in cancer progression was unclear. As a PhD student in Dr. Craig Thompson’s laboratory, I provided the first evidence for a causal role of IDH1/2 mutations in cell differentiation blockade and tumorigenesis and uncovered an unexpected function of 2HG in inhibiting histone and DNA demethylation. These results not only support a causal role for metabolic reprogramming in tumorigenesis, but also suggest that chromatin regulators can act as sensors of metabolic intermediates, linking cell metabolism to epigenetic control of gene expression. Recently, this notion has received increasing recognition in the fields of cancer, stem cell, and aging biology. The clinical impact of these studies is demonstrated by the FDA-approved mutant IDH2 inhibitor, which exhibits anti-leukemic effects by reversing aberrant chromatin modifications and restoring the differentiation capacity of leukemia cells.