IDH1 K224 acetylation promotes colorectal cancer via miR-9-5p/NHE1 axis-mediated regulation of acidic microenvironment

Bo Wang; Long Zhao; Changjiang Yang; Yilin Lin; Shan Wang; Yingjiang Ye; Jianyuan Luo; Zhanlong Shen

iScience (Jul 2023)

IDH1 K224 acetylation promotes colorectal cancer via miR-9-5p/NHE1 axis-mediated regulation of acidic microenvironment

Bo Wang,
Long Zhao,
Changjiang Yang,
Yilin Lin,
Shan Wang,
Yingjiang Ye,
Jianyuan Luo,
Zhanlong Shen

Affiliations

Bo Wang: Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People’s Hospital, No.11 Xizhimen South Street, Beijing 100044, P.R. China
Long Zhao: Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People’s Hospital, No.11 Xizhimen South Street, Beijing 100044, P.R. China
Changjiang Yang: Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People’s Hospital, No.11 Xizhimen South Street, Beijing 100044, P.R. China
Yilin Lin: Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People’s Hospital, No.11 Xizhimen South Street, Beijing 100044, P.R. China
Shan Wang: Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People’s Hospital, No.11 Xizhimen South Street, Beijing 100044, P.R. China
Yingjiang Ye: Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People’s Hospital, No.11 Xizhimen South Street, Beijing 100044, P.R. China
Jianyuan Luo: Department of Medical Genetics, Peking University Health Science Center, Beijing 100191, P.R. China
Zhanlong Shen: Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People’s Hospital, No.11 Xizhimen South Street, Beijing 100044, P.R. China; Corresponding author

Journal volume & issue: Vol. 26, no. 7
p. 107206

Abstract

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Summary: The acidic microenvironment is considered an important factor in colorectal cancer (CRC) that contributes to malignant transformation. However, the underlying mechanism remains unclear. In a previous study, we confirmed that IDH1 K224 deacetylation promotes enzymatic activity and the production of α-KG. Here, we further investigate the effect of IDH1 hyperacetylation on the CRC acidic microenvironment. We demonstrate that increased α-KG affects hydroxylation of Ago2 and mediates miR-9-5p targeting NHE1 protein. Knockdown of NHE1 dramatically attenuates CRC cell proliferation and migration by restricting transport of intracellular H+ out of cells. Furthermore, we show that miR-9-5p is the microRNA with the most significant difference in the alteration of IDH1 K224 acetylation and can downregulate NHE1 mRNA. Our data also indicate that hydroxylation stabilizes Ago2, which in turn promotes miR-9-5p activity. Taken together, our results reveal a novel mechanism through which IDH1 deacetylation regulates the cellular acidic microenvironment and inhibits CRC metastasis.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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