TY - JOUR
T1 - TGF-β-dependent reprogramming of amino acid metabolism induces epithelial–mesenchymal transition in non-small cell lung cancers
AU - Nakasuka, Fumie
AU - Tabata, Sho
AU - Sakamoto, Takeharu
AU - Hirayama, Akiyoshi
AU - Ebi, Hiromichi
AU - Yamada, Tadaaki
AU - Umetsu, Ko
AU - Ohishi, Maki
AU - Ueno, Ayano
AU - Goto, Hisatsugu
AU - Sugimoto, Masahiro
AU - Nishioka, Yasuhiko
AU - Yamada, Yasuhiro
AU - Tomita, Masaru
AU - Sasaki, Atsuo T.
AU - Yano, Seiji
AU - Soga, Tomoyoshi
N1 - Funding Information:
We thank K. Igarashi and R. Hayasaka for technical assistance, and Drs. T. Nishihara and T. Ishikawa for helpful discussions and insights. This study was supported by the Japan Society for the Promotion of Science KAKENHI (16K21361, S.T.; 17KK0199, S.T.; 19J22093, F.N.), the Naito Foundation (S.T.), the Mori Memorial Research fund (F.N.), the Yamagishi Student Project Support Program of Keio University (F.N.), the NIH National Institute of Neurological Disorder and Stroke (R01NS089815, A.T.S.), Extramural Collaborative Research Grant of Cancer Research Institute, Kanazawa University (S.T.), and the research funds from the Yamagata Prefecture Government and City of Tsuruoka, Japan (S.T., A.H., M.S., M.T., and T. Soga).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Epithelial–mesenchymal transition (EMT)—a fundamental process in embryogenesis and wound healing—promotes tumor metastasis and resistance to chemotherapy. While studies have identified signaling components and transcriptional factors responsible in the TGF-β-dependent EMT, whether and how intracellular metabolism is integrated with EMT remains to be fully elucidated. Here, we showed that TGF-β induces reprogramming of intracellular amino acid metabolism, which is necessary to promote EMT in non-small cell lung cancer cells. Combined metabolome and transcriptome analysis identified prolyl 4-hydroxylase α3 (P4HA3), an enzyme implicated in cancer metabolism, to be upregulated during TGF-β stimulation. Further, knockdown of P4HA3 diminished TGF-β-dependent changes in amino acids, EMT, and tumor metastasis. Conversely, manipulation of extracellular amino acids induced EMT-like responses without TGF-β stimulation. These results suggest a previously unappreciated requirement for the reprogramming of amino acid metabolism via P4HA3 for TGF-β-dependent EMT and implicate a P4HA3 inhibitor as a potential therapeutic agent for cancer.
AB - Epithelial–mesenchymal transition (EMT)—a fundamental process in embryogenesis and wound healing—promotes tumor metastasis and resistance to chemotherapy. While studies have identified signaling components and transcriptional factors responsible in the TGF-β-dependent EMT, whether and how intracellular metabolism is integrated with EMT remains to be fully elucidated. Here, we showed that TGF-β induces reprogramming of intracellular amino acid metabolism, which is necessary to promote EMT in non-small cell lung cancer cells. Combined metabolome and transcriptome analysis identified prolyl 4-hydroxylase α3 (P4HA3), an enzyme implicated in cancer metabolism, to be upregulated during TGF-β stimulation. Further, knockdown of P4HA3 diminished TGF-β-dependent changes in amino acids, EMT, and tumor metastasis. Conversely, manipulation of extracellular amino acids induced EMT-like responses without TGF-β stimulation. These results suggest a previously unappreciated requirement for the reprogramming of amino acid metabolism via P4HA3 for TGF-β-dependent EMT and implicate a P4HA3 inhibitor as a potential therapeutic agent for cancer.
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U2 - 10.1038/s42003-021-02323-7
DO - 10.1038/s42003-021-02323-7
M3 - Article
C2 - 34168290
AN - SCOPUS:85108863135
SN - 2399-3642
VL - 4
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 782
ER -
