Abstract
BackgroundTargeting mitochondrial oncoproteins presents a new concept in the development of effective cancer therapeutics. ATAD3A is a nuclear-encoded mitochondrial enzyme contributing to mitochondrial dynamics, cholesterol metabolism, and signal transduction. However, its impact and underlying regulatory mechanisms in cancers remain ill-defined.MethodsWe used head and neck squamous cell carcinoma (HNSCC) as a research platform and achieved gene depletion by lentiviral shRNA and CRISPR/Cas9. Molecular alterations were examined by RNA-sequencing, phospho-kinase profiling, Western blotting, RT-qPCR, immunohistochemistry, and immunoprecipitation. Cancer cell growth was assessed by MTT, colony formation, soft agar, and 3D cultures. The therapeutic efficacy in tumor development was evaluated in orthotopic tongue tumor NSG mice.ResultsATAD3A is highly expressed in HNSCC tissues and cell lines. Loss of ATAD3A expression suppresses HNSCC cell growth and elicits tumor regression in orthotopic tumor-bearing mice, whereas gain of ATAD3A expression produces the opposite effects. From a mechanistic perspective, the tumor suppression induced by the overexpression of the Walker A dead mutant of ATAD3A (K358) produces a potent dominant-negative effect due to defective ATP-binding. Moreover, ATAD3A binds to ERK1/2 in the mitochondria of HNSCC cells in the presence of VDAC1, and this interaction is essential for the activation of mitochondrial ERK1/2 signaling. Most importantly, the ATAD3A-ERK1/2 signaling axis drives HNSCC development in a RAS-independent fashion and, thus, tumor suppression is more effectively achieved when ATAD3A knockout is combined with RAS inhibitor treatment.ConclusionsThese findings highlight the novel function of ATAD3A in regulating mitochondrial ERK1/2 activation that favors HNSCC development. Combined targeting of ATAD3A and RAS signaling may potentiate anticancer activity for HNSCC therapeutics.
Highlights
Targeting mitochondrial oncoproteins presents a new concept in the development of effective cancer therapeutics
High expression levels of ATPase family AAA-domain containing protein 3A (ATAD3A) are associated with human head and neck squamous cell carcinoma (HNSCC) development Investigation of ATAD3A expression levels from TCGA Pan-Cancer analysis revealed that ATAD3A was highly expressed in many types of cancer, including HNSCC (Fig. 1A), which was confirmed by data from the Oncomine database (Supplementary Fig. S1A)
We examined the distribution of ATAD3A expression levels within TCGA HNSCC cases
Summary
Targeting mitochondrial oncoproteins presents a new concept in the development of effective cancer therapeutics. As a result, promising treatments that precisely target the specific mitochondrial proteins involved in tumor development and progression are greatly needed. It is clear, that understanding these cancer-associated mitochondrial proteins is the first step in the development of mitochondria-based anticancer regimens. The ATPase family AAA-domain containing protein 3A (ATAD3A), a nuclear-encoded mitochondrial enzyme, is anchored to the mitochondrial inner membrane (MIM) with its N-terminus in contact with the mitochondrial outer membrane (MOM) [1, 3,4,5] This protein contains two coiled-coil domains (CC1 and CC2), Walker A (WA) and Walker B (WB) motifs, among which, the WA motif is responsible for ATP binding in the AAA module of ATAD3A [1, 6]. Of particular relevance to the essential processes underlying mitochondrial biogenesis, metabolism and mitophagy, ATAD3A has been considered one of most common genes linked to mitochondrial diseases in childhood, and deletion of ATAD3A and its orthologues in flies, worms, and mammals leads to embryonic lethality with growth retardation and aberrant mitochondrial activity [1, 9,10,11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
