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The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer

Author

Listed:
  • Chi Chun Wong

    (The Chinese University of Hong Kong)

  • Jian-Lin Wu

    (Macau University of Science and Technology)

  • Fenfen Ji

    (The Chinese University of Hong Kong)

  • Wei Kang

    (The Chinese University of Hong Kong)

  • Xiqing Bian

    (Macau University of Science and Technology)

  • Huarong Chen

    (The Chinese University of Hong Kong)

  • Lam-Shing Chan

    (The Chinese University of Hong Kong)

  • Simson Tsz Yat Luk

    (The Chinese University of Hong Kong)

  • Samuel Tong

    (The Chinese University of Hong Kong)

  • Jiaying Xu

    (The Chinese University of Hong Kong)

  • Qiming Zhou

    (The Chinese University of Hong Kong)

  • Dabin Liu

    (The Chinese University of Hong Kong)

  • Hao Su

    (The Chinese University of Hong Kong)

  • Hongyan Gou

    (The Chinese University of Hong Kong)

  • Alvin Ho-Kwan Cheung

    (The Chinese University of Hong Kong)

  • Ka Fai To

    (The Chinese University of Hong Kong)

  • Zongwei Cai

    (Hong Kong Baptist University)

  • Jerry W. Shay

    (University of Texas Southwestern Medical Center)

  • Jun Yu

    (The Chinese University of Hong Kong)

Abstract

Therapeutic targeting of KRAS-mutant colorectal cancer (CRC) is an unmet need. Here, we show that Proprotein Convertase Subtilisin/Kexin type 9 (PSCK9) promotes APC/KRAS-mutant CRC and is a therapeutic target. Using CRC patient cohorts, isogenic cell lines and transgenic mice, we identify that de novo cholesterol biosynthesis is induced in APC/KRAS mutant CRC, accompanied by increased geranylgeranyl diphosphate (GGPP)─a metabolite necessary for KRAS activation. PCSK9 is the top up-regulated cholesterol-related gene. PCSK9 depletion represses APC/KRAS-mutant CRC cell growth in vitro and in vivo, whereas PCSK9 overexpression induces oncogenesis. Mechanistically, PCSK9 reduces cholesterol uptake but induces cholesterol de novo biosynthesis and GGPP accumulation. GGPP is a pivotal metabolite downstream of PCSK9 by activating KRAS/MEK/ERK signaling. PCSK9 inhibitors suppress growth of APC/KRAS-mutant CRC cells, organoids and xenografts, especially in combination with simvastatin. PCSK9 overexpression predicts poor survival of APC/KRAS-mutant CRC patients. Together, cholesterol homeostasis regulator PCSK9 promotes APC/KRAS-mutant CRC via GGPP-KRAS/MEK/ERK axis and is a therapeutic target.

Suggested Citation

  • Chi Chun Wong & Jian-Lin Wu & Fenfen Ji & Wei Kang & Xiqing Bian & Huarong Chen & Lam-Shing Chan & Simson Tsz Yat Luk & Samuel Tong & Jiaying Xu & Qiming Zhou & Dabin Liu & Hao Su & Hongyan Gou & Alvi, 2022. "The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31663-z
    DOI: 10.1038/s41467-022-31663-z
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    References listed on IDEAS

    as
    1. Xinjian Liu & Xuhui Bao & Mengjie Hu & Hanman Chang & Meng Jiao & Jin Cheng & Liyi Xie & Qian Huang & Fang Li & Chuan-Yuan Li, 2020. "Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer," Nature, Nature, vol. 588(7839), pages 693-698, December.
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