ASC modulates HIF-1α stability and induces cell mobility in OSCC

Abstract

High-level expression of ASC (Apoptosis-associated speck-like protein containing a CARD) leads to lymph node metastasis in OSCC, but the underlying mechanism remains unclear. Here, we show that HIF-1α participates in ASCinduced metastasis. We identified 195 cell-motion-associated genes that were highly activated in ASC-overexpressed SAS_ASC cells; of them, 14 representative genes were found to be overexpressed in OSCC tissues in our previously reported RNA-seq dataset, OSCC-Taiwan. Nine of the 14 genes were also upregulated in OSCC-TCGA samples. Among the nine genes, RRAS2, PDGFA, and VEGFA, were correlated with poor overall survival of patients in OSCC-TCGA dataset. We further demonstrated that the promoters of these 14 ASC-induced genes contained binding motifs for the transcription-regulating factor, HIF-1α. We observed that ASC interacted with and stabilized HIF-1α in both the cytoplasm and the nucleus under normoxia. Molecules involved in the HIF-1α pathway, such as VHL and PHD2, showed no difference in their gene and protein levels in the presence or absence of ASC, but the expression of HIF-1α-OH, and the ubiquitination of HIF-1α were both decreased in SAS_ASC cells versus SAS_con cells. The migration and invasion activities of SAS_ASC cells were reduced when cells were treated with the HIF-1α synthesis inhibitor, digoxin. Taken together, our results demonstrate that the novel ASC-HIF-1α regulatory pathway contributes to lymph node metastasis in OSCC, potentially suggesting a new treatment strategy for OSCC.

Combined effects of hyperthermia and chemotherapy on the regulate autophagy of oral squamous cell carcinoma cells under a hypoxic microenvironment

“…As an adaptive response to hypoxic stress, hypoxic tumor cells activate several survival pathways to carry out their essential biological processes compared with normal cells. The hypoxia-inducible factor-1α (HIF-1α) is one crucial facilitator for energy adaption and oxygen metabolic stress in hypoxia and nutrition deficiency tumor environment, and functions as a general regulator of tumor aggressiveness and metastasis as well [ 4 , 6 , 7 ].…”

Uncoupled pyroptosis and IL-1β secretion downstream of inflammasome signaling

“…In addition to versatile functions in inflammasomeindependent biological processes (195)(196)(197)(198)(199)(200), ASC has established its central role in inflammasome signaling. Briefly, ASC connects the inflammasome sensor and caspase-1 via homotypic interactions of CARD-CARD and PYD-PYD, hierarchically organizing and densely packing the ternary inflammasome complex into a micrometer-sized disk-like structure that is denoted a pyroptosome or an ASC speck.…”

The Interplay of Hypoxia Signaling on Mitochondrial Dysfunction and Inflammation in Cardiovascular Diseases and Cancer: From Molecular Mechanisms to Therapeutic Approaches

“…Furthermore, the same HIF-1α can be regulated by NLRP3. In this case, it has been observed that the adaptor protein ASC associates and stabilizes HIF-1α to increase cell migration and metastasis in oral squamous cell carcinoma [ 78 ]. However, other investigations demonstrate that hypoxia may be a repressor of NLRP3.…”