1. Academic Validation
  2. Reprogramming of palmitic acid induced by dephosphorylation of ACOX1 promotes β-catenin palmitoylation to drive colorectal cancer progression

Reprogramming of palmitic acid induced by dephosphorylation of ACOX1 promotes β-catenin palmitoylation to drive colorectal cancer progression

  • Cell Discov. 2023 Mar 7;9(1):26. doi: 10.1038/s41421-022-00515-x.
Qiang Zhang 1 Xiaoya Yang 1 Jinjie Wu 1 2 Shubiao Ye 2 Junli Gong 1 2 Wai Ming Cheng 2 Zhanhao Luo 2 Jing Yu 1 2 Yugeng Liu 3 Wanyi Zeng 1 Chen Liu 1 2 Zhizhong Xiong 2 Yuan Chen 1 Zhen He 4 5 Ping Lan 6 7
Affiliations

Affiliations

  • 1 The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 2 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China.
  • 3 Center for Synthetic Microbiome, Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China.
  • 4 The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China. hezh5@mail.sysu.edu.cn.
  • 5 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China. hezh5@mail.sysu.edu.cn.
  • 6 The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China. lanping@mail.sysu.edu.cn.
  • 7 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China. lanping@mail.sysu.edu.cn.
Abstract

Metabolic reprogramming is a hallmark of Cancer. However, it is not well known how metabolism affects Cancer progression. We identified that metabolic Enzyme acyl-CoA oxidase 1 (ACOX1) suppresses colorectal Cancer (CRC) progression by regulating palmitic acid (PA) reprogramming. ACOX1 is highly downregulated in CRC, which predicts poor clinical outcome in CRC patients. Functionally, ACOX1 depletion promotes CRC cell proliferation in vitro and colorectal tumorigenesis in mouse models, whereas ACOX1 overexpression inhibits patient-derived xenograft growth. Mechanistically, DUSP14 dephosphorylates ACOX1 at serine 26, promoting its polyubiquitination and proteasomal degradation, thereby leading to an increase of the ACOX1 substrate PA. Accumulated PA promotes β-catenin cysteine 466 palmitoylation, which inhibits CK1- and GSK3-directed phosphorylation of β-catenin and subsequent β-Trcp-mediated proteasomal degradation. In return, stabilized β-catenin directly represses ACOX1 transcription and indirectly activates DUSP14 transcription by upregulating c-Myc, a typical target of β-catenin. Finally, we confirmed that the DUSP14-ACOX1-PA-β-catenin axis is dysregulated in clinical CRC samples. Together, these results identify ACOX1 as a tumor suppressor, the downregulation of which increases PA-mediated β-catenin palmitoylation and stabilization and hyperactivates β-catenin signaling thus promoting CRC progression. Particularly, targeting β-catenin palmitoylation by 2-bromopalmitate (2-BP) can efficiently inhibit β-catenin-dependent tumor growth in vivo, and pharmacological inhibition of DUSP14-ACOX1-β-catenin axis by Nu-7441 reduced the viability of CRC cells. Our results reveal an unexpected role of PA reprogramming induced by dephosphorylation of ACOX1 in activating β-catenin signaling and promoting Cancer progression, and propose the inhibition of the dephosphorylation of ACOX1 by DUSP14 or β-catenin palmitoylation as a viable option for CRC treatment.

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