PGC1α inhibits melanoma metastasis independent of its role in mitochondrial energetic metabolism.
Major finding: PGC1α inhibits melanoma metastasis independent of its role in mitochondrial energetic metabolism.
Mechanism: PGC1α promotes expression of ID2, which inhibits TCF4 to suppress integrin expression.
Impact: Targeting components of the PGC1α signaling cascade may suppress melanoma metastasis.
PGC1α is a transcriptional coactivator involved in mitochondrial biogenesis and metabolic reprogramming in melanoma. Although it has been linked to poor prognosis, its expression has also been associated with less invasive growth, prompting Luo, Lim, and colleagues to explore the role of PGC1α in melanoma metastasis. PGC1α depletion increased expression of prometastatic genes, increased expression of integrins, and promoted activation of the downstream focal adhesion kinase, resulting in enhanced cell migration and invasion. In vivo, PGC1α suppression resulted in highly metastatic melanoma cells and widespread disease. In contrast, expression of PGC1α in PGC1α-negative cells reduced integrin expression and invasion. Melanoma cells exhibited heterogeneous PGC1α expression and mitochondria number. The mitochondrialo/PGC1αlo population of cells displayed enhanced expression of prometastatic genes, whereas the mitochondriahi/PGC1αhi population exhibited enhanced proliferation. PGC1α bound at the promoter and increased expression of Inhibitor of DNA binding 2 (ID2), and, like PGC1α depletion, ID2 depletion promoted lung metastasis. Moreover, expression of ID2 in PGC1α-deficient cells suppressed the prometastatic gene programs and reduced metastasis, suggesting that ID2 acts downstream of PGC1α to suppress metastasis. Mechanistically, ID2 bound to and inactivated the transcription factor TCF4, thereby reducing integrin expression and suppressing metastasis. Of note, suppression of ID2 or TCF4 did not affect cellular metabolism, indicating that the role of PGC1α in suppressing metastasis is distinct from its role in metabolism. Treatment with a BRAFV600E inhibitor increased expression of PGC1α and ID2, and reduced TCF4 occupancy at integrin gene promoters, resulting in their downregulation. Further, vemurafenib suppressed melanoma metastasis in vivo, but its effects were reduced when PGC1α or ID2 were depleted. Together, these results indicate that targeting components of the PGC1α–ID2–TCF4–integrin signaling pathway may suppress melanoma metastasis, and suggest that early use of BRAFV600E inhibitors may have the potential to reduce metastasis.
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