KRAS mutation increases histone H3 lysine 9 lactylation (H3K9la) to promote colorectal cancer progression by facilitating cholesterol transporter GRAMD1A expression

Chi Zhang; Runfeng Yu; Senmao Li; Ming Yuan; Tuo Hu; Jiaqi Liu; Haoxian Ke; Shubiao Ye; Jihye Yun; Junfeng Huang; Guanzhan Liang; Shaopeng Chen; Xianrui Wu; Ping Lan

doi:10.1038/s41418-025-01533-4

KRAS mutation increases histone H3 lysine 9 lactylation (H3K9la) to promote colorectal cancer progression by facilitating cholesterol transporter GRAMD1A expression

Cell Death Differ. 2025 Jul 24. doi: 10.1038/s41418-025-01533-4. Online ahead of print.

Authors

Chi Zhang^#^{1

2

3}, Runfeng Yu^#^{1

2

3}, Senmao Li^#⁴, Ming Yuan^#^{1

2

3}, Tuo Hu^{1

2

3}, Jiaqi Liu^{1

2

3

5}, Haoxian Ke⁴, Shubiao Ye^{1

2

3}, Jihye Yun⁶, Junfeng Huang^{1

2

3}, Guanzhan Liang^{1

2

3}, Shaopeng Chen^{1

2

3}, Xianrui Wu⁷, Ping Lan^{8

9

10

11}

Affiliations

¹ Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
² Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
³ Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
⁴ Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
⁵ Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
⁶ Department of Genetics, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA.
⁷ Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. wuxianr5@mail.sysu.edu.cn.
⁸ Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. lanping@mail.sysu.edu.cn.
⁹ Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. lanping@mail.sysu.edu.cn.
¹⁰ Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. lanping@mail.sysu.edu.cn.
¹¹ State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China. lanping@mail.sysu.edu.cn.

^# Contributed equally.

PMID: 40707783
DOI: 10.1038/s41418-025-01533-4

Abstract

Histone lactylation is a novel epigenetic modification derived from lactate, but its role and mechanism in KRAS mutant colorectal cancer (CRC) progression remains to be fully elucidated. In this study, we first showed that mutant KRAS increased H3 lysine 9 lactylation (H3K9la) to promote CRC progression. We found that KRAS-mutant CRC tissues and cell lines exhibited higher lactylation and H3K9la levels compared to KRAS wild-type counterparts, driven by increased intracellular lactate. Elevated lactylation and H3K9la levels were associated with poor prognosis and advanced clinical stages. Inhibition of lactylation and H3K9la suppressed proliferation and migration of CRC cells. Mechanistically, mutant KRAS upregulated GRAMD1A expression by elevating H3K9la levels to increase chromatin accessibility. And increased GRAMD1A facilitated cholesterol metabolism to promote CRC growth and metastasis. Targeted inhibition of H3K9la or GRAMD1A reduced tumor growth in CRC patient-derived xenografts (PDX) models. Our study uncovered the critical role of H3K9la as a novel epigenetic modification in KRAS mutant CRC progression, suggesting H3K9la and its downstream gene GRAMD1A as promising targets for therapeutic intervention in KRAS mutant CRC and potential biomarkers for the prognosis of CRC patients.