Epigenetically upregulated WIPF1 plays a major role in BRAF V600E-promoted papillary thyroid cancer aggressiveness

Tao Zhang, Xiaopei Shen, Rengyun Liu, Guangwu Zhu, Justin Bishop, Mingzhao Xing

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

How the BRAF V600E mutation promotes the pathogenesis and aggressiveness of papillary thyroid cancer (PTC) is not completely understood. Here we explored a novel mechanism involving WASP interacting protein family member 1 (WIPF1). In PTC tumors, compared with the wild-type BRAF, BRAF V600E was associated with over-expression and hypomethylation of the WIPF1 gene. In thyroid cancer cell lines with wild-type BRAF, WIPF1 expression was robustly upregulated upon introduced expression of BRAF V600E (P=0.03) whereas the opposite was seen upon BRAF knockdown or treatment with BRAF V600E or MEK inhibitors in cells harboring BRAF V600E. Methylation of a functionally critical region of the WIPF1 promoter was decreased by expressing BRAF V600E in cells harboring the wild-type BRAF and increased by BRAF knockdown or treatment with BRAF V600E or MEK inhibitors in cells harboring BRAF V600E mutation. Under-expression and hypermethylation of WIPF1 induced by stable BRAF knockdown was reversed by DNA demethylating agent 5'-azadeoxycytidine. Knockdown of WIPF1 robustly inhibited anchorage-independent colony formation, migration, and invasion of thyroid cancer cells and suppressed xenograft thyroid cancer tumor growth and vascular invasion, mimicking the effects of BRAF knockdown. In human PTC tumors, WIPF1 expression was associated with extrathyroidal invasion (P=0.01) and lymph node metastasis (P=2.64E-05). In summary, BRAF V600E-activated MAP kinase pathway causes hypomethylation and overexpression of WIPF1; WIPF1 then functions like an oncoprotein to robustly promote aggressive cellular and tumor behaviors of PTC. This represents a novel mechanism in BRAF V600E-promoted PTC aggressiveness and identifies WIPF1 as a novel therapeutic target for thyroid cancer.

Original languageEnglish (US)
Pages (from-to)900-914
Number of pages15
JournalOncotarget
Volume8
Issue number1
DOIs
StatePublished - Jan 1 2017

Fingerprint

Wiskott-Aldrich Syndrome Protein Family
Thyroid Neoplasms
Mitogen-Activated Protein Kinase Kinases
decitabine
Neoplasms
Papillary Thyroid cancer
Mutation
Oncogene Proteins
Heterografts
Methylation
Blood Vessels

Keywords

  • BRAF V600E
  • Oncogenesis
  • Thyroid cancer
  • Tumor aggressiveness
  • WIPF1

ASJC Scopus subject areas

  • Oncology

Cite this

Epigenetically upregulated WIPF1 plays a major role in BRAF V600E-promoted papillary thyroid cancer aggressiveness. / Zhang, Tao; Shen, Xiaopei; Liu, Rengyun; Zhu, Guangwu; Bishop, Justin; Xing, Mingzhao.

In: Oncotarget, Vol. 8, No. 1, 01.01.2017, p. 900-914.

Research output: Contribution to journalArticle

Zhang, Tao ; Shen, Xiaopei ; Liu, Rengyun ; Zhu, Guangwu ; Bishop, Justin ; Xing, Mingzhao. / Epigenetically upregulated WIPF1 plays a major role in BRAF V600E-promoted papillary thyroid cancer aggressiveness. In: Oncotarget. 2017 ; Vol. 8, No. 1. pp. 900-914.
@article{d96c1c7d9fe74b3296abe9245334ea04,
title = "Epigenetically upregulated WIPF1 plays a major role in BRAF V600E-promoted papillary thyroid cancer aggressiveness",
abstract = "How the BRAF V600E mutation promotes the pathogenesis and aggressiveness of papillary thyroid cancer (PTC) is not completely understood. Here we explored a novel mechanism involving WASP interacting protein family member 1 (WIPF1). In PTC tumors, compared with the wild-type BRAF, BRAF V600E was associated with over-expression and hypomethylation of the WIPF1 gene. In thyroid cancer cell lines with wild-type BRAF, WIPF1 expression was robustly upregulated upon introduced expression of BRAF V600E (P=0.03) whereas the opposite was seen upon BRAF knockdown or treatment with BRAF V600E or MEK inhibitors in cells harboring BRAF V600E. Methylation of a functionally critical region of the WIPF1 promoter was decreased by expressing BRAF V600E in cells harboring the wild-type BRAF and increased by BRAF knockdown or treatment with BRAF V600E or MEK inhibitors in cells harboring BRAF V600E mutation. Under-expression and hypermethylation of WIPF1 induced by stable BRAF knockdown was reversed by DNA demethylating agent 5'-azadeoxycytidine. Knockdown of WIPF1 robustly inhibited anchorage-independent colony formation, migration, and invasion of thyroid cancer cells and suppressed xenograft thyroid cancer tumor growth and vascular invasion, mimicking the effects of BRAF knockdown. In human PTC tumors, WIPF1 expression was associated with extrathyroidal invasion (P=0.01) and lymph node metastasis (P=2.64E-05). In summary, BRAF V600E-activated MAP kinase pathway causes hypomethylation and overexpression of WIPF1; WIPF1 then functions like an oncoprotein to robustly promote aggressive cellular and tumor behaviors of PTC. This represents a novel mechanism in BRAF V600E-promoted PTC aggressiveness and identifies WIPF1 as a novel therapeutic target for thyroid cancer.",
keywords = "BRAF V600E, Oncogenesis, Thyroid cancer, Tumor aggressiveness, WIPF1",
author = "Tao Zhang and Xiaopei Shen and Rengyun Liu and Guangwu Zhu and Justin Bishop and Mingzhao Xing",
year = "2017",
month = "1",
day = "1",
doi = "10.18632/oncotarget.13400",
language = "English (US)",
volume = "8",
pages = "900--914",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "1",

}

TY - JOUR

T1 - Epigenetically upregulated WIPF1 plays a major role in BRAF V600E-promoted papillary thyroid cancer aggressiveness

AU - Zhang, Tao

AU - Shen, Xiaopei

AU - Liu, Rengyun

AU - Zhu, Guangwu

AU - Bishop, Justin

AU - Xing, Mingzhao

PY - 2017/1/1

Y1 - 2017/1/1

N2 - How the BRAF V600E mutation promotes the pathogenesis and aggressiveness of papillary thyroid cancer (PTC) is not completely understood. Here we explored a novel mechanism involving WASP interacting protein family member 1 (WIPF1). In PTC tumors, compared with the wild-type BRAF, BRAF V600E was associated with over-expression and hypomethylation of the WIPF1 gene. In thyroid cancer cell lines with wild-type BRAF, WIPF1 expression was robustly upregulated upon introduced expression of BRAF V600E (P=0.03) whereas the opposite was seen upon BRAF knockdown or treatment with BRAF V600E or MEK inhibitors in cells harboring BRAF V600E. Methylation of a functionally critical region of the WIPF1 promoter was decreased by expressing BRAF V600E in cells harboring the wild-type BRAF and increased by BRAF knockdown or treatment with BRAF V600E or MEK inhibitors in cells harboring BRAF V600E mutation. Under-expression and hypermethylation of WIPF1 induced by stable BRAF knockdown was reversed by DNA demethylating agent 5'-azadeoxycytidine. Knockdown of WIPF1 robustly inhibited anchorage-independent colony formation, migration, and invasion of thyroid cancer cells and suppressed xenograft thyroid cancer tumor growth and vascular invasion, mimicking the effects of BRAF knockdown. In human PTC tumors, WIPF1 expression was associated with extrathyroidal invasion (P=0.01) and lymph node metastasis (P=2.64E-05). In summary, BRAF V600E-activated MAP kinase pathway causes hypomethylation and overexpression of WIPF1; WIPF1 then functions like an oncoprotein to robustly promote aggressive cellular and tumor behaviors of PTC. This represents a novel mechanism in BRAF V600E-promoted PTC aggressiveness and identifies WIPF1 as a novel therapeutic target for thyroid cancer.

AB - How the BRAF V600E mutation promotes the pathogenesis and aggressiveness of papillary thyroid cancer (PTC) is not completely understood. Here we explored a novel mechanism involving WASP interacting protein family member 1 (WIPF1). In PTC tumors, compared with the wild-type BRAF, BRAF V600E was associated with over-expression and hypomethylation of the WIPF1 gene. In thyroid cancer cell lines with wild-type BRAF, WIPF1 expression was robustly upregulated upon introduced expression of BRAF V600E (P=0.03) whereas the opposite was seen upon BRAF knockdown or treatment with BRAF V600E or MEK inhibitors in cells harboring BRAF V600E. Methylation of a functionally critical region of the WIPF1 promoter was decreased by expressing BRAF V600E in cells harboring the wild-type BRAF and increased by BRAF knockdown or treatment with BRAF V600E or MEK inhibitors in cells harboring BRAF V600E mutation. Under-expression and hypermethylation of WIPF1 induced by stable BRAF knockdown was reversed by DNA demethylating agent 5'-azadeoxycytidine. Knockdown of WIPF1 robustly inhibited anchorage-independent colony formation, migration, and invasion of thyroid cancer cells and suppressed xenograft thyroid cancer tumor growth and vascular invasion, mimicking the effects of BRAF knockdown. In human PTC tumors, WIPF1 expression was associated with extrathyroidal invasion (P=0.01) and lymph node metastasis (P=2.64E-05). In summary, BRAF V600E-activated MAP kinase pathway causes hypomethylation and overexpression of WIPF1; WIPF1 then functions like an oncoprotein to robustly promote aggressive cellular and tumor behaviors of PTC. This represents a novel mechanism in BRAF V600E-promoted PTC aggressiveness and identifies WIPF1 as a novel therapeutic target for thyroid cancer.

KW - BRAF V600E

KW - Oncogenesis

KW - Thyroid cancer

KW - Tumor aggressiveness

KW - WIPF1

UR - http://www.scopus.com/inward/record.url?scp=85009727500&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85009727500&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.13400

DO - 10.18632/oncotarget.13400

M3 - Article

C2 - 27863429

AN - SCOPUS:85009727500

VL - 8

SP - 900

EP - 914

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 1

ER -