Abstract
Metastasis associates with late stages of lung cancer progression and remains the main cause of patient death due to the lack of clinically effective therapeutics. Here we report that the transcription factor GATA3 and its co-factor FOG2 commonly promote the expression of the lysyl hydroxylase (LH) family members, including LH2 and LH3, which in turn drive lung adenocarcinoma cell migration, invasion, and metastasis. We show evidence that both LH2 and LH3 are direct transcription targets for GATA3. Knockdown of either LH2 or LH3 suppresses migration and invasion; on the contrary, forced expression of LH2 or LH3 promotes growth and migration, suggesting that the two LHs exert redundant oncogenic functions. Importantly, re-expression of LH2 is sufficient to restore the metastatic capacity of GATA3-depleted cells, suggesting a role for LHs as the downstream mediators of GATA3. Collectively, our data reveal a pro-metastatic GATA3-LHs axis for lung cancer, supporting the notion that targeting LHs may be useful for treating lung cancer.
Highlights
Lung cancer is the deadliest malignancy worldwide and causes ~1.5 million deaths each year according to the WHO statistics
Our previous studies have shown that knockdown of GATA3 and its co-factor friend of GATA 2 (FOG2) suppresses spontaneous metastasis of 344SQ lung adenocarcinoma cells in syngeneic models of metastasis[19,20]
Our sequencing results revealed that the mRNA expression levels of more than 700 genes were commonly changed upon the knockdown of FOG2 and GATA3 (Supplemental Fig. 2B)
Summary
Lung cancer is the deadliest malignancy worldwide and causes ~1.5 million deaths each year according to the WHO statistics (www.who.int). We have shown that GATA3 may act as a downstream mediator of the NOTCH ligand JAGGED2 to promote tumor cell migration, invasion, and dissemination, by binding to the promoter and silencing the transcription of microRNA-200 (miR-200), a small non-coding RNA that exerts tumor suppressive functions in KRAS mutant lung cancer cells[15,16,17,18]. Consistent with these findings, we found that the friend of GATA 2 (FOG2), a co-factor for GATA factors, is highly expressed by mesenchymal-like lung adenocarcinoma www.nature.com/scientificreports/. Our findings suggest that LHs are pro-metastatic mediators of FOG2 and GATA3 and may be useful candidate therapeutic targets for treating lung cancer
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