Hanyang Dong

All Publications

• SETD2 suppresses tumorigenesis in a KRASG12C-driven lung cancer model, and its catalytic activity is regulated by histone acetylation. eLife Mack, R. J., Flores, N. M., Fox, G. C., Dong, H., Cebeci, M., Hausmann, S., Chasan, T., Dowen, J. M., Strahl, B. D., Mazur, P. K., Gozani, O. 2025; 14

  Abstract

  Histone H3 trimethylation at lysine 36 (H3K36me3) is a key chromatin modification that regulates fundamental physiological and pathological processes. In humans, SETD2 is the only known enzyme that catalyzes H3K36me3 in somatic cells and is implicated in tumor suppression across multiple cancer types. While there is considerable crosstalk between the SETD2-H3K36me3 axis and other epigenetic modifications, much remains to be understood. Here, we show that Setd2 functions as a potent tumor suppressor in a KRASG12C-driven lung adenocarcinoma (LUAD) mouse model, and that acetylation enhances SETD2 in vitro methylation of H3K36 on nucleosome substrates. In vivo, Setd2 ablation accelerates lethality in an autochthonous KRASG12C-driven LUAD mouse tumor model. Biochemical analyses reveal that polyacetylation of histone tails in a nucleosome context promotes H3K36 methylation by SETD2. In addition, monoacetylation exerts position-specific effects to stimulate SETD2 methylation activity. In contrast, mono-ubiquitination at various histone sites, including at H2AK119 and H2BK120, does not affect SETD2 methylation of nucleosomes. Together, these findings provide insight into how SETD2 integrates histone modification signals to regulate H3K36 methylation and highlights the potential role of SETD2-associated epigenetic crosstalk in cancer pathogenesis.

  View details for DOI 10.7554/eLife.107451

  View details for PubMedID 40948406

  View details for PubMedCentralID PMC12435893

• NSD2 inhibitors rewire chromatin to treat lung and pancreatic cancers. Nature Jeong, J., Hausmann, S., Dong, H., Szczepski, K., Flores, N. M., Garcia Gonzalez, A., Shi, L., Lu, X., Lempiäinen, J., Jakab, M., Zeng, L., Chasan, T., Bareke, E., Dong, R., Carlson, E., Padilla, R., Husmann, D., Thompson, J., Shipman, G. A., Zahn, E., Barnes, C. A., Khan, L. F., Albertorio-Sáez, L. M., Brill, E., Kumary, V. U., Marunde, M. R., Maryanski, D. N., Szany, C. C., Venters, B. J., Windham, C. L., Nowakowski, M. E., Czaban, I., Jaremko, M., Keogh, M. C., Le, K., Soth, M. J., Garcia, B. A., Jaremko, Ł., Majewski, J., Mazur, P. K., Gozani, O. 2025

  Abstract

  NSD2 catalyses the epigenetic modification H3K36me2 (refs. 1,2) and is a candidate convergent downstream effector of oncogenic signalling in diverse malignancies3-5. However, it remains unclear whether the enzymatic activity of NSD2 is therapeutically targetable. Here we characterize a series of clinical-grade small-molecule catalytic NSD2 inhibitors (NSD2i) and show that the pharmacological targeting of NSD2 constitutes an epigenetic dependency with broad therapeutic efficacy in KRAS-driven preclinical cancer models. NSD2i inhibits NSD2 with single-digit nanomolar half-maximal inhibitory concentration potency and high selectivity over related methyltransferases. Structural analyses reveal that the specificity of NSD2i for NSD2 is due to competitive binding with S-adenosylmethionine and catalytic disruption through a binary-channel obstruction mechanism. Proteo-epigenomic and single-cell strategies in pancreatic and lung cancer models support a mechanism in which sustained NSD2i exposure reverses pathological H3K36me2-driven chromatin plasticity, re-establishing silencing at H3K27me3-legacy loci to curtail oncogenic gene expression programs. Accordingly, NSD2i impairs the viability of pancreatic and lung cancer cells and the growth of patient-derived xenograft tumours. Furthermore, NSD2i, which is well-tolerated in vivo, prolongs survival in advanced-stage autochthonous KRASG12C-driven pancreatic and lung tumours in mouse models to a comparable level as KRAS inhibition with sotorasib6. In these models, treatment with both a NSD2 inhibitor and sotorasib synergize to confer sustained survival with extensive tumour regression and elimination. Together, our work uncovers targeting of the NSD2-H3K36me2 axis as an actionable vulnerability in difficult to treat cancers and provides support for the evaluation of NSD2 and KRAS inhibitor combination therapies in a clinical setting.

  View details for DOI 10.1038/s41586-025-09299-y

  View details for PubMedID 40770093

  View details for PubMedCentralID 2797197

• SETD2 suppresses tumorigenesis in a KRASG12C-driven lung cancer model and its catalytic activity is regulated by histone acetylation. bioRxiv : the preprint server for biology Mack, R. J., Flores, N. M., Fox, G. C., Dong, H., Cebeci, M., Hausmann, S., Chasan, T., Dowen, J. M., Strahl, B. D., Mazur, P. K., Gozani, O. 2025

  Abstract

  Histone H3 trimethylation at lysine 36 (H3K36me3) is a key chromatin modification that regulates fundamental physiologic and pathologic processes. In humans, SETD2 is the only known enzyme that catalyzes H3K36me3 in somatic cells and is implicated in tumor suppression across multiple cancer types. While there is considerable crosstalk between the SETD2-H3K36me3 axis and other epigenetic modifications, much remains to be understood. Here, we show that SETD2 functions as a potent tumor suppressor in a KRASG12C-driven lung adenocarcinoma (LUAD) mouse model, and that acetylation at H3K27 (H3K27ac) enhances SETD2 in vitro methylation of H3K36 on nucleosome substrates. In vivo, SETD2 ablation accelerates lethality in an autochthonous KRASG12C-driven LUAD mouse tumor model. Biochemical analyses reveal that polyacetylation of histone tails in a nucleosome context promote H3K36 methylation by SETD2. In addition, monoacetylation exerts position-specific effects to stimulate SETD2 methylation activity. In contrast, mono-ubiquitination at various histone sites, including at H2AK119 and H2BK120, does not affect SETD2 methylation of nucleosomes. Together, these findings provide insight into how SETD2 integrates histone modification signals to regulate H3K36 methylation and highlights the potential role of SETD2-associated epigenetic crosstalk in cancer pathogenesis.

  View details for DOI 10.1101/2025.05.16.654513

  View details for PubMedID 40462961

  View details for PubMedCentralID PMC12132414