MYC Indirectly Represses YAP/TAZ Activity in Mammary Tumors

During development, the transcription factor MYC, which drives proliferation and regulates various cellular processes such as growth and apoptosis, promotes the expansion and differentiation of progenitor populations, resulting in depletion of the quiescent stem cell population. To elucidate the role of MYC-driven transcriptional programs in stem cell maintenance, von Eyss and colleagues transduced human mammary epithelial cells (HMLE), which exhibit the self-renewal properties of mammary stem cells and form mammospheres in culture, to inducibly express MYC. Expression of MYC ablated the sphere-forming potential of CD44^hi/CD24^lo HMLEs, and RNA sequencing and MYC chromatin immunoprecipitation sequencing (ChIP-seq) revealed that the induction of MYC specifically repressed expression of the target genes of yes-associated protein 1 (YAP1) and tafazzin (TAZ) in the CD44^hi/CD24^lo population. The authors showed that MYC inhibited YAP/TAZ activity in CD44^hi/CD24^lo HMLEs in vitro and mammary stem cells in vivo by driving the expression of phospholipase D family, member 6 (PLD6), and not via large tumor suppressor kinase 1 (LATS) and RHO GTPase, two known upstream regulators of YAP/TAZ activity. Mechanistically, MYC-induced upregulation of PLD6, which facilitates mitochondrial fusion, led to activation of 5′ AMP-activated protein kinase (AMPK), which phosphorylated YAP and subsequently prevented transcription of YAP/TAZ target genes. To ascertain the role of this mechanism in tumorigenesis, a dominant-negative MYC allele was inducibly expressed in a transgenic Wnt mouse model, which resulted in differentiated tumors that exhibited decreased proliferation and AMPK activity, and increased nuclear YAP. Consistent with these findings, both MYC and PLD6 were highly expressed in tumors from patients with triple-negative breast cancer and predictive for poor patient prognosis, and elevated PLD6 expression correlated with high MYC activity and decreased YAP/TAZ activity. Together, these results identify a negative regulatory pathway inhibiting YAP activity that is mediated by a MYC-induced transcriptional program of growth in mammary tumors.

Von Eyss B, Jaenicke LA, Kortlever RM, Royla N, Wiese KE, Letschert S, et al. A MYC-driven change in mitochondrial dynamics limits YAP/TAZ function in mammary epithelial cells and breast cancer. Cancer Cell 2015;28:743–57.

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