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

Wong, Chi Chun, Wu, Jian-Lin, Ji, Fenfen, Kang, Wei, Bian, Xiqing, Chen, Huarong, Chan, Lam-Shing, Luk, Simson Tsz Yat, Tong, Samuel, Xu, Jiaying, Zhou, Qiming, Liu, Dabin, Su, Hao, Gou, Hongyan, Cheung, Alvin Ho-Kwan, To, Ka Fai, Cai, Zongwei, Shay, Jerry W., Yu, Jun·2022·Nature Communications
DOI 10.1038/s41467-022-31663-zPMC PMC9270407
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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.

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Research works printed but not linked: 29

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Metadata

Authors
Wong, C. C., Wu, J.-L., Ji, F., Kang, W., Bian, X., Chen, H., Chan, L.-S., Luk, S. T. Y., Tong, S., Xu, J., Zhou, Q., Liu, D., Su, H., Gou, H., Cheung, A. H.-K., To, K. F., Cai, Z., Shay, J. W., & Yu, J.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-07-08
Volume
13
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-022-31663-z
PMC
PMC9270407
Cited by
103
References
2
Language
en
Licence

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