A feedback regulation between Kindlin-2 and GLI1 in prostate cancer cells

Jianchao Gao; Ammad Aslam Khan; Takashi Shimokawa; Jun Zhan; Staffan Strömblad; Weigang Fang; Hongquan Zhang

doi:10.1016/j.febslet.2012.12.028

A feedback regulation between Kindlin-2 and GLI1 in prostate cancer cells

FEBS Lett. 2013 Mar 18;587(6):631-8. doi: 10.1016/j.febslet.2012.12.028. Epub 2013 Jan 18.

Authors

Jianchao Gao¹, Ammad Aslam Khan, Takashi Shimokawa, Jun Zhan, Staffan Strömblad, Weigang Fang, Hongquan Zhang

Affiliation

¹ Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Health Science Center, #38 Xue Yuan Road, Beijing 100191, China.

PMID: 23337877
DOI: 10.1016/j.febslet.2012.12.028

Abstract

Kindlin-2 is engaged in tumor progression. However, the mechanism accounting for Kindlin-2 regulation in tumor cells remained largely unknown. Here, we report a regulatory loop between Kindlin-2 and GLI1, an effector of Hedgehog signaling pathway. We show that Kindlin-2 is transcriptionally downregulated via GLI1 occupancy on the Kindlin-2 promoter. Adversely, we found that Kindlin-2 promotes GLI1 expression through a mechanism involving GSK3β inactivation and is independent of Smoothened. Functionally, knockdown of Kindlin-2 cooperates with cyclopamine, a Smoothened antagonist, to decrease the viability of prostate cancer cells. Taken together, targeting the Kindlin-2-GLI1 feedback loop may facilitate the killing of prostate cancer cells.

Publication types

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

MeSH terms

Cell Line, Tumor
Cell Survival / drug effects
Feedback, Physiological* / drug effects
Gene Expression Regulation, Neoplastic* / drug effects
Gene Knockdown Techniques
Glycogen Synthase Kinase 3 / genetics
Glycogen Synthase Kinase 3 / metabolism
Glycogen Synthase Kinase 3 beta
Humans
Male
Membrane Proteins / genetics*
Membrane Proteins / metabolism
Neoplasm Proteins / genetics*
Neoplasm Proteins / metabolism
Promoter Regions, Genetic
Prostatic Neoplasms / genetics*
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / metabolism
Signal Transduction / drug effects
Smoothened Receptor
Transcription Factors / genetics*
Transcription Factors / metabolism
Transcription, Genetic / drug effects
Veratrum Alkaloids / pharmacology
Zinc Finger Protein GLI1

Substances

FERMT3 protein, human
GLI1 protein, human
Membrane Proteins
Neoplasm Proteins
Receptors, G-Protein-Coupled
SMO protein, human
Smoothened Receptor
Transcription Factors
Veratrum Alkaloids
Zinc Finger Protein GLI1
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
Glycogen Synthase Kinase 3
cyclopamine