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Despite significant progress in the cancer field, tumor cell invasion and metastasis remain a major clinical challenge. Cell invasion across tissue boundaries depends largely on extracellular matrix degradation, which can be initiated by formation of actin-rich cell structures specialized in matrix degradation called invadopodia. Although the hypoxic microenvironment within solid tumors has been increasingly recognized as an important driver of local invasion and metastasis, little is known about how hypoxia influences invadopodia biogenesis. Here, we show that histone deacetylase 6 (HDAC6), a cytoplasmic member of the histone deacetylase family, is a novel modulator of hypoxia-induced invadopodia formation. Hypoxia was found to enhance HDAC6 tubulin deacetylase activity through activation of the EGFR pathway. Activated HDAC6, in turn, triggered Smad3 phosphorylation resulting in nuclear accumulation. Inhibition of HDAC6 activity or knockdown of the protein inhibited both hypoxia-induced Smad3 activation and invadopodia formation. Our data provide evidence that hypoxia influences invadopodia formation in a biphasic manner, which involves the activation of HDAC6 deacetylase activity by EGFR, resulting in enhanced Smad phosphorylation and nuclear accumulation. The identification of HDAC6 as a key participant of hypoxia-induced cell invasion may have important therapeutic implications for the treatment of metastasis in cancer patients. [ABSTRACT FROM AUTHOR]

Tumor hypoxia is strongly associated with malignant progression such as increased cell invasion and metastasis. Although the invasion-related genes affected by hypoxia have been well described, the contribution of post-transcriptional mechanisms such as protein trafficking and proprotein processing associated with the hypoxic response remains poorly understood. The proprotein convertase furin, the major processing enzyme of the secretory pathway, resides in the trans-Golgi network and most studies support a model where endogenous substrates are processed by furin within this compartment. Here, we report that hypoxia triggered an unexpected relocalization of furin from the trans-Golgi network to endosomomal compartments and the cell surface in cancer cells. Exposing these cells back to normoxic conditions reversed furin redistribution, suggesting that the tumor microenvironment modulates furin trafficking in a highly regulated manner. Assessment of the mechanisms involved revealed that both Rab4GTPase-dependent recycling and interaction of furin with the cytoskeletal anchoring protein, filamin-A, are essential for the cell surface relocalization of furin. Interference with the association of furin with filamin-A, prevented cell surface relocalization of furin and abolished the ability of cancer cells to migrate in response to hypoxia. Our observations support the notion that hypoxia promotes the formation of a peripheral processing compartment where furin translocates for enhanced processing of proproteins involved in tumorigenesis. J. Cell. Physiol. 227: 789-800, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]