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

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, Alvin Ho-Kwan Cheung, Ka Fai To, Zongwei Cai, Jerry W. Shay and Jun Yu ()
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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

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31663-z

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