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; Jun Yu

doi:10.1038/s41467-022-31663-z

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
, Jun Yu^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › peer-review

68 Citations (Scopus)

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.

Original language	English
Article number	3971
Journal	Nature Communications
Volume	13
Issue number	1
Early online date	8 Jul 2022
DOIs	https://doi.org/10.1038/s41467-022-31663-z
Publication status	Published - Dec 2022

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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. (2022). The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer. Nature Communications, 13(1), Article 3971. https://doi.org/10.1038/s41467-022-31663-z

@article{0180d62e7e034f858a56cadbb44764e3,

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

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.",

author = "Wong, \{Chi Chun\} and Wu, \{Jian Lin\} and Fenfen Ji and Wei Kang and Xiqing Bian and Huarong Chen and Chan, \{Lam Shing\} and Luk, \{Simson Tsz Yat\} and Samuel Tong and Jiaying Xu and Qiming Zhou and Dabin Liu and Hao Su and Hongyan Gou and Cheung, \{Alvin Ho Kwan\} and To, \{Ka Fai\} and Zongwei Cai and Shay, \{Jerry W.\} and Jun Yu",

note = "This project was supported by funds from Research Grants Council-General Research Fund (24100520, C.C.W.; 14101917, C.C.W.; 14108718, C.C.W.), Research Grants Council-Collaborative Research Fund (C4039-19G, J.Y.); Heath and Medical Research Fund (06170686, C.C.W.; 08190706, C.C.W.); the Macau Science and Technology Development Fund (009/20176/A1, J.L.W.). Science and Technology Program Grant Shenzhen (JCYJ20170413161534162, J.Y.). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-31663-z",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

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Wong, CC, Wu, JL, Ji, F, Kang, W, Bian, X, Chen, H, Chan, LS, Luk, STY, Tong, S, Xu, J, Zhou, Q, Liu, D, Su, H, Gou, H, Cheung, AHK, To, KF, Cai, Z, Shay, JW & Yu, J 2022, 'The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer', Nature Communications, vol. 13, no. 1, 3971. https://doi.org/10.1038/s41467-022-31663-z

TY - JOUR

T1 - The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer

AU - Wong, Chi Chun

AU - Wu, Jian Lin

AU - Ji, Fenfen

AU - Kang, Wei

AU - Bian, Xiqing

AU - Chen, Huarong

AU - Chan, Lam Shing

AU - Luk, Simson Tsz Yat

AU - Tong, Samuel

AU - Xu, Jiaying

AU - Zhou, Qiming

AU - Liu, Dabin

AU - Su, Hao

AU - Gou, Hongyan

AU - Cheung, Alvin Ho Kwan

AU - To, Ka Fai

AU - Cai, Zongwei

AU - Shay, Jerry W.

AU - Yu, Jun

N1 - This project was supported by funds from Research Grants Council-General Research Fund (24100520, C.C.W.; 14101917, C.C.W.; 14108718, C.C.W.), Research Grants Council-Collaborative Research Fund (C4039-19G, J.Y.); Heath and Medical Research Fund (06170686, C.C.W.; 08190706, C.C.W.); the Macau Science and Technology Development Fund (009/20176/A1, J.L.W.). Science and Technology Program Grant Shenzhen (JCYJ20170413161534162, J.Y.). Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85133693961

U2 - 10.1038/s41467-022-31663-z

DO - 10.1038/s41467-022-31663-z

M3 - Journal article

C2 - 35803966

AN - SCOPUS:85133693961

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3971

ER -

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

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