Hedgehog pathway orchestrates the interplay of histone modifications and tailors combination epigenetic therapies in breast cancer

Xiaomin Wang; Jun Xu; Yiming Sun; Siyuwei Cao; Hanlin Zeng; Nan Jin; Matthew Shou; Shuai Tang; Yi Chen; Min Huang

doi:10.1016/j.apsb.2023.03.009

Hedgehog pathway orchestrates the interplay of histone modifications and tailors combination epigenetic therapies in breast cancer

Acta Pharm Sin B. 2023 Jun;13(6):2601-2612. doi: 10.1016/j.apsb.2023.03.009. Epub 2023 Mar 11.

Authors

Xiaomin Wang^{1

2}, Jun Xu^{1

2}, Yiming Sun¹, Siyuwei Cao¹, Hanlin Zeng¹, Nan Jin¹, Matthew Shou³, Shuai Tang¹, Yi Chen^{1

2}, Min Huang^{1

2

4}

Affiliations

¹ Cancer Research Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
² University of Chinese Academy of Sciences, Beijing 100049, China.
³ Division of Diabetes, Endocrinology and Metabolism, Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁴ School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.

Abstract

Epigenetic therapies that cause genome-wide epigenetic alterations, could trigger local interplay between different histone marks, leading to a switch of transcriptional outcome and therapeutic responses of epigenetic treatment. However, in human cancers with diverse oncogenic activation, how oncogenic pathways cooperate with epigenetic modifiers to regulate the histone mark interplay is poorly understood. We herein discover that the hedgehog (Hh) pathway reprograms the histone methylation landscape in breast cancer, especially in triple-negative breast cancer (TNBC). This facilitates the histone acetylation caused by histone deacetylase (HDAC) inhibitors and gives rise to new therapeutic vulnerability of combination therapies. Specifically, overexpression of zinc finger protein of the cerebellum 1 (ZIC1) in breast cancer promotes Hh activation, facilitating the switch of H3K27 methylation (H3K27me) to acetylation (H3K27ac). The mutually exclusive relationship of H3K27me and H3K27ac allows their functional interplay at oncogenic gene locus and switches therapeutic outcomes. Using multiple in vivo breast cancer models including patient-derived TNBC xenograft, we show that Hh signaling-orchestrated H3K27me and H3K27ac interplay tailors combination epigenetic drugs in treating breast cancer. Together, this study reveals the new role of Hh signaling-regulated histone modifications interplay in responding to HDAC inhibitors and suggests new epigenetically-targeted therapeutic solutions for treating TNBC.

Keywords: Breast cancer; Combination therapy; Drug resistance; Epigenetic interplay; HDAC inhibitors; Hedgehog pathway; Histone acetylation; Histone methylation; LIFR; ZIC1.