Gankyrin activates mTORC1 signaling by accelerating TSC2 degradation in colorectal cancer

Xiaoyu Qin; Xinxin Wang; Feng Liu; Laura E Morris; Xiaowen Wang; Bin Jiang; Yanjie Zhang

doi:10.1016/j.canlet.2016.03.013

Gankyrin activates mTORC1 signaling by accelerating TSC2 degradation in colorectal cancer

Cancer Lett. 2016 Jun 28;376(1):83-94. doi: 10.1016/j.canlet.2016.03.013. Epub 2016 Mar 11.

Authors

Xiaoyu Qin¹, Xinxin Wang¹, Feng Liu¹, Laura E Morris², Xiaowen Wang², Bin Jiang¹, Yanjie Zhang³

Affiliations

¹ Oncology Department, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201900, China.
² Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
³ Oncology Department, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201900, China. Electronic address: zhangyanjie@shsmu.edu.cn.

PMID: 26975632
DOI: 10.1016/j.canlet.2016.03.013

Abstract

Gankyrin is overexpressed in some malignancies. However its roles in colorectal carcinogenesis and underlying mechanisms remain largely unexplored. Here we report that gankyrin promotes the initiation and development of colorectal carcinogenesis by activating mTORC1 signaling through TSC/Rheb dependent mechanism. We further show that Gankyrin overexpression accelerated TSC2 degradation, while knockdown in a panel of colorectal cancer (CRC) cell lines, cell line derived xenografts and CRC patient derived xenograft (PDX) tumors delayed TSC2 degradation, restored the TSC2 protein level, and inhibited mTORC1 signaling and CRC growth. Our findings reveal a unique mechanism by which gankyrin promotes colorectal carcinogenesis and show that gankyrin is a potential therapeutic target to improve the clinical management of CRC.

Keywords: Colorectal cancer; Gankyrin; TSC2; mTOR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation
Colorectal Neoplasms / enzymology*
Colorectal Neoplasms / genetics
Colorectal Neoplasms / mortality
Colorectal Neoplasms / pathology
Enzyme Activation
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Heterografts
Humans
Kaplan-Meier Estimate
Mechanistic Target of Rapamycin Complex 1
Mice, Inbred BALB C
Mice, Nude
Monomeric GTP-Binding Proteins / metabolism
Multiprotein Complexes / metabolism*
Neoplasm Transplantation
Neuropeptides / metabolism
Prognosis
Proteasome Endopeptidase Complex / genetics
Proteasome Endopeptidase Complex / metabolism*
Proteolysis
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism*
Ras Homolog Enriched in Brain Protein
Signal Transduction
TOR Serine-Threonine Kinases / metabolism*
Time Factors
Transfection
Tuberous Sclerosis Complex 2 Protein
Tumor Burden
Tumor Suppressor Proteins / metabolism*
Up-Regulation

Substances

Multiprotein Complexes
Neuropeptides
PSMD10 protein, human
Proto-Oncogene Proteins
RHEB protein, human
Ras Homolog Enriched in Brain Protein
TSC2 protein, human
Tsc2 protein, mouse
Tuberous Sclerosis Complex 2 Protein
Tumor Suppressor Proteins
Mechanistic Target of Rapamycin Complex 1
TOR Serine-Threonine Kinases
Proteasome Endopeptidase Complex
Monomeric GTP-Binding Proteins