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    
     
  29 November 2016  
 
Activation of mutant TERT promoter by RAS-ERK signalling is a key step in malignant progression of BRAF-mutant human melanomas
 
 




Authors

Yinghui Li1,*, Hui Shan Cheng1, Wee Joo Chng2-4, Vinay Tergaonkar1,5,6*

1  Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and    Research), Singapore 138673.
2  Cancer Science Institute of Singapore, National University of Singapore, Singapore 117597.
3  Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore    117597.
4  Department of Haematology-Oncology, National University Cancer Institute of Singapore, National    University Health System, Singapore 117597.
5  Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS),    Singapore 117597.
6  Centre for Cancer Biology , University of South Australia and SA Pathology, Adelaide, SA5000,    Australia.

*Correspondence: Vinay Tergaonkar vinayt@imcb.a-star.edu.sg and Yinghui Li liyh@imcb.a-star.edu.sg

Institute of Molecular and Cell Biology (A*STAR), Proteos, 61, Biopolis Drive, 138673, Singapore. Phone +65-65869836; Fax +65-67791117


Published online in PNAS on November 23, 2016, doi:10.1073/pnas.1611106113.

Abstract
Although activating BRAF/NRAS mutations are frequently seen in melanomas, they are not sufficient to drive malignant transformation and require additional events. Frequent co-occurrence of mutations in the promoter for telomerase reverse transcriptase (TERT), along with BRAF alterations, has recently been noted and correlated with poorer prognosis, implicating a functional link between BRAF signalling and telomerase reactivation in melanomas. Here, we report that RAS-ERK signalling in BRAF mutant melanomas is critical for regulating active chromatin state and recruitment of RNA polymerase II at mutant TERT promoters. Our study provides evidence that the mutant TERT promoter is a key substrate downstream of RAS-ERK pathway. Reactivating TERT and hence reconstituting telomerase is an important step in melanoma progression from non-malignant nevi with BRAF mutations. Hence, combined targeting of RAS-ERK and TERT promoter remodelling is a promising avenue to limit long-term survival of a majority of melanomas which harbour these two mutations.



Figure Legend:
A model for TERT reactivation at mutant TERT promoter during constitutive RAS-ERK signalling in BRAF-mutant melanoma tumours. In BRAF V600E-mutant melanocytic lesions, ERK2 does not bind WT TERT promoter, which is transcriptionally repressed due to the recruitment of HDAC1 complex by Sp1 . Hence, RAS-ERK signalling does not activate TERT expression in the absence of TERT promoter mutations and these precursor lesions remain as benign melanocytic nevi. However when BRAF mutant tumours attain TERT promoter mutations, RAS-ERK hyperactivation leads to the association of ERK2 to mutant TERT promoter, potentially through GABPA or Ets1 interaction, and its subsequent phosphorylation of Sp1 stabilizes it on the mutant promoter. Stabilised ERK on the mutant TERT promoter facilitates the dissociation of HDAC1 from mutant TERT promoters, thereby promoting histone 3 lysine 9 acetylation which generates an active chromatin state that mediates TERT reactivation. This results in the sustained telomerase activity of tumour cells which promotes their development to malignant melanomas.

For more information on Vinay TERGAONKAR’s lab, please click here.