News archives


OCTOBER - DECEMBER 17

JULY - SEPTEMBER 17

APRIL - JUNE 17

JANUARY - MARCH 17

OCTOBER - DECEMBER 16

JULY - SEPTEMBER 16

APRIL - JUNE 16

JANUARY - MARCH 16

OCTOBER - DECEMBER 15

JULY - SEPTEMBER 15

APRIL - JUNE 15

JANUARY - MARCH 15

OCTOBER - DECEMBER 14

JULY - SEPTEMBER 14

APRIL - JUNE 14

JANUARY - MARCH 14

OCTOBER - DECEMBER 13

JULY - SEPTEMBER 13

APRIL - JUNE 13

JANUARY - MARCH 13

OCTOBER - DECEMBER 12

JULY - SEPTEMBER 12

APRIL - JUNE 12

JANUARY - MARCH 12

OCTOBER - DECEMBER 11

JULY - SEPTEMBER 11

APRIL - JUNE 11

JANUARY - MARCH 11

OCTOBER - DECEMBER 10

JULY - SEPTEMBER 10

APRIL - JUNE 10

JANUARY - MARCH 10

OCTOBER - DECEMBER 09

JULY - SEPTEMBER 09

APRIL - JUNE 09

JANUARY - MARCH 09

OCTOBER - DECEMBER 08

JULY - SEPTEMBER 08

APRIL - JUNE 08

JANUARY - MARCH 08

OCTOBER - DECEMBER 07

JULY - SEPTEMBER 07

APRIL - JUNE 07

JANUARY - MARCH 07

 
  current news   Press   selected story    
     
  3 November 2017  
 
Deubiquitinating Enzyme USP9X Suppresses Tumor Growth via LATS kinase and Core Components of the Hippo pathway
 
 




Authors
Aleksandra Toloczko1,2,5, Fusheng Guo1,5, Hiu-Fung Yuen1, Qing Wen3, Stephen A. Wood4, Yan Shan Ong1, Pei Yi Chan1, Asfa Alli Shaik1, Jayantha Gunaratne1, Mark J. Dunne2, Wanjin Hong1,6 and Siew Wee Chan1,6

Author Affiliations
1  Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR),    Singapore, Republic of Singapore
2  ISchool of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United    Kingdom
3  ICentre for Public Health and Centre for Cancer Research & Cell Biology, School of Medicine, Dentistry    and Biomedical Sciences, Queen’s University Belfast, Belfast, United Kingdom
4  Eskitis Institute for Drug Discovery, Griffith University, Queensland, Australia
5  These authors contributed equally to this work
6  Corresponding authors: mcbcsw@imcb.a-star.edu.sg (Siew Wee Chan), mcbhwj@imcb.a-star.edu.sg    (Wanjin Hong).

Published in Cancer Research, 77(18):4921-4933 on September 15, 2017

Abstract
The core LATS kinases of the Hippo tumor suppressor pathway phosphorylate and inhibit the downstream transcriptional co-activators YAP and TAZ, which are implicated in various cancers. Recent studies have identified various E3 ubiquitin ligases that negatively regulate the Hippo pathway via ubiquitination, yet few deubiquitinating enzymes (DUB) have been implicated. In this study, we report the DUB USP9X is an important regulator of the core kinases of this pathway. USP9X interacted strongly with LATS kinase and to a lesser extent with WW45, KIBRA, and Angiomotin, and LATS co-migrated exclusively with USP9X during gel filtration chromatography analysis. Knockdown of USP9X significantly downregulated and destabilized LATS and resulted in enhanced nuclear translocation of YAP and TAZ, accompanied with activation of their target genes. In the absence of USP9X, cells exhibited an epithelial-to-mesenchymal transition phenotype, acquired anchorage-independent growth in soft agar, and led to enlarged, disorganized, three-dimensional acini. YAP/TAZ target gene activation in response to USP9X knockdown was suppressed by knockdown of YAP, TAZ, and TEAD2. Deletion of USP9X in mouse embryonic fibroblasts resulted in significant downregulation of LATS. Furthermore, USP9X protein expression correlated positively with LATS but negatively with YAP/TAZ in pancreatic cancer tissues as well as pancreatic and breast cancer cell lines. Overall, these results strongly indicate that USP9X potentiates LATS kinase to suppress tumor growth.

Figure

Figure legend
: (A) Knockdown of USP9X (USP9X-KD) in MCF10A cells resulted in epithelial-mesenchymal transition (EMT). (B) Three-dimensional culture of USP9X-KD cells in matrigel. USP9X-KD acini have enlarged and disorganized morphology. (C) Immunohistochemical (IHC) staining of USP9X and LATS in normal and pancreatic cancer tissue arrays. USP9X and LATS protein expression were predominantly negative in pancreatic cancer tissues. (D) USP9X and LATS were expressed weakly as opposed to strong YAP/TAZ expression in tissue sections derived from pancreatic cancer patients.

For more information on Wanjin HONG's lab, please click here.
For more information on Jayantha GUNARATNE's lab, please click here.