Open AccessSpecific activation of glycolytic enzyme enolase 2 in BRAF V600E‐mutated colorectal cancer
Author(s) -
Yukimoto Ryohei,
Nishida Naohiro,
Hata Tsuyoshi,
Fujino Shiki,
Ogino Takayuki,
Miyoshi Norikatsu,
Takahashi Hidekazu,
Uemura Mamoru,
Satoh Taroh,
Hirofumi Yamamoto,
Mizushima Tsunekazu,
Doki Yuichiro,
Eguchi Hidetoshi
Publication year - 2021
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14929
Subject(s) - cancer research , v600e , colorectal cancer , forkhead transcription factors , biology , enolase , gene knockdown , mutation , cancer , transcription factor , gene , immunohistochemistry , immunology , genetics
The BRAF V600E mutation occurs in approximately 10% of patients with metastatic colorectal cancer (CRC) and constitutes a distinct subtype of the disease with extremely poor prognosis. To address this refractory disease, we investigated the unique metabolic gene profile of BRAF V600E‐mutated tumors via in silico analysis using a large‐scale clinical database. We found that BRAF V600E‐mutated tumors exhibited a specific metabolic gene expression signature, including some genes that are associated with poor prognosis in CRC. We discovered that BRAF V600E‐mutated tumors expressed high levels of glycolytic enzyme enolase 2 (ENO2), which is mainly expressed in neuronal tissues under physiological conditions. In vitro experiments using CRC cells demonstrated that BRAF V600E‐mutated cells exhibited enhanced dependency on ENO2 compared to BRAF wild‐type cancer cells and that knockdown of ENO2 led to the inhibition of proliferation and migration of BRAF V600E‐mutated cancer cells. Moreover, inhibition of ENO2 resulted in enhanced sensitivity to vemurafenib, a selective inhibitor of BRAF V600E. We identified AP‐1 transcription factor subunit (FOSL1) as being involved in the transcription of ENO2 in CRC cells. In addition, both MAPK and PI3K/Akt signaling were suppressed upon inhibition of ENO2, implying an additional oncogenic role of ENO2. These results suggest the crucial role of ENO2 in the progression of BRAF V600E‐mutated CRC and indicate the therapeutic implications of targeting this gene.