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

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

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 (US)
Article number	3971
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-31663-z
State	Published - Dec 2022

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

Access to Document

10.1038/s41467-022-31663-z

Cite this

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

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

@article{8b15dbdb54784307b253a62c1bf78d7a,

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 = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

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

language = "English (US)",

volume = "13",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

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

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 - http://www.scopus.com/inward/record.url?scp=85133693961&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85133693961&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-31663-z

DO - 10.1038/s41467-022-31663-z

M3 - 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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this