The Role of Histone Cleavage in Breast Cancer

Dana-Farber Cancer Inst, Boston MA

Investigators

Abstract

PROJECT SUMMARY Perturbed epigenetic programs play key roles in tumorigenesis and epigenetic regulators are commonly mutated in cancer. The KDM4C histone demethylase is amplified and overexpressed in a subset of triple-negative breast cancer (TNBC), a tumor subtype with high propensity to treatment resistance and distant metastasis. KDM4C demethylates histone H3 lysine 9 tri-methyl (H3K9me3) and lysine 36 tri-methyl (H3K36me3), but whether this activity is required for its tumorigenic function is not known. KDM4C is frequently co-amplified with JAK2, CD274 (PD-L1) and PDCD1LG2 (PD-L2). Deciphering mechanisms by which KDM4C drives tumor growth will further our understanding of the role of mutant epigenetic regulators in cancer and pave the way for treatment strategies targeting KDM4C-dependent tumors. In the K99 phase, I will test the hypothesis that KDM4C drives tumor growth by preventing the proteolytic cleavage of the N-terminal tail of histone H3 by cathepsin L (CTSL) (Aim 1). This hypothesis is based on my preliminary data demonstrating growth inhibition, activation of CTSL, and N- terminal clipping of histone H3 after genetic or pharmacologic blockade of KDM4C in KDM4C-amplified breast cancer cell lines. I will generate and characterize KDM4C-dependent and independent cell models expressing N-terminal truncated or CTSL-cleavage-resistant histone H3. I will also investigate whether KDM4C modulates CTSL activity via acting on it directly as its non-histone substrate or indirectly through modulating H3K9me3 and H3K36me3 (Aim 2). In the R00 phase, I will explore functional synergies between KDM4C and JAK2-STAT3 signaling and test if their combined inhibition is more effective in 9p24 amplified tumors (Aim 3). In summary, this proposal aims to leverage innovative models and state-of-the-art genomic profiling and screens to decipher novel epigenetic regulatory mechanisms and treatment strategies targeting the KDM4C nexus. I am committed to pursuing high impact translational cancer research focused on improving patient care. I have a long-term interest in breast cancer epigenetics with the goal of developing novel therapies. My immediate goals are to expand my experimental and bioinformatic skills by performing CRISPR screen and multiplexed immunofluorescence and analyzing complex multi-omic datasets. I will also improve my skills in scientific communication and lab management. My further training will be conducted under the mentorship of Dr. Kornelia Polyak, a breast cancer expert in the Dana-Farber Cancer Institute; a fantastic research environment that fosters collaboration between researchers and clinicians, has a multitude of state-of-the-art facilities, and has outstanding programs to enhance my scientific and career development. I have assembled an outstanding Scientific Advisory Committee consisting of Drs. Myles Brown, Bradley Bernstein, Nancy Lin, and Clifford Meyer, leaders in the cancer epigenetics, breast oncology, and computational biology fields. My strong scientific background, excellent mentorship team, and outstanding institutional environment will ensure the successful completion of the proposed study and my transition to independent faculty position.