Loss-of-function of IFT88 determines metabolic phenotypes in thyroid cancer

Abstract

Primary cilia are microtubule-based, dynamic organelles characterized by continuous assembly and disassembly. The intraflagellar transport (IFT) machinery, including IFT88 in cilia, is involved in the maintenance of bidirectional motility along the axonemes, which is required for ciliogenesis and functional competence. Cancer cells are frequently associated with loss of primary cilia and IFT functions. However, there is little information on the role of IFT88 or primary cilia in the metabolic remodeling of cancer cells. Therefore, we investigated the cellular and metabolic effects of the loss-of-function (LOF) mutations of IFT88/primary cilia in thyroid cancer cells. IFT88-deficient 8505C thyroid cancer cells were generated using the CRISPR/Cas9 system, and RNA-sequencing analysis was performed. LOF of the IFT88 gene resulted in a marked defect in ciliogenesis and mitochondrial oxidative function. Gene expression patterns in IFT88-deficient thyroid cancer cells favored glycolysis and lipid biosynthesis. However, LOF of IFT88/primary cilia did not promote thyroid cancer cell proliferation, migration, and invasion. The results suggest that IFT88/primary cilia play a role in metabolic reprogramming in thyroid cancer cells.

Primary Cilium in Cancer Hallmarks

“…A recent paper has innovatively investigated the metabolic effects subsequent to the loss of cilia in IFT88 -deficient thyroid cancer cells. The authors provided evidence that the loss of function (LOF) of IFT88 /primary cilia results in mitochondrial dysfunction in favor of glycolytic metabolism and lipid biosynthesis [171]. LOF- IFT88 /primary cilia resulted in mitochondrial fragmentation, impaired oxidative phosphorylation (OXPHOS), diminished mitochondrial membrane potential, and reduced ATP synthesis.…”

Isoform-specific aPKC renders primary cilia dispensable for Hedgehog signaling and basal cell carcinoma growth

“…So primary cilia loss in advanced tumors is unexpected from a mechanistic view. Disruption of primary cilia have been observed in many advanced cancers, including cancers of the brain (Han et al, 2009), breast (Menzl et al, 2014), kidney (Schraml et al, 2009), skin (Zingg et al, 2018), pancreas (Seeley et al, 2009), thyroid (Lee et al, 2018;Menzl et al, 2014), ovary (Egeberg et al, 2012), and prostate (Hassounah et al, 2013). How primary cilia loss benefits tumor growth is unclear.…”

Dissecting the Vesicular Trafficking Function of IFT Subunits

“…It is difficult to determine that an observed phenotype owes to defective cilia or/and some defective extraciliary function (Baldari and Rosenbaum, 2010;Yuan and Sun, 2013;Vertii et al, 2015;Hua and Ferland, 2018a,b). Extraciliary functions of the ciliary proteins have been reported to be involved in various aspects of cell activities, such as cell cycle regulation (Qin et al, 2007), cytoskeletal and migration regulation (Nishita et al, 2017), establishment of polarity (Toriyama et al, 2016), cellular metabolism (Lee et al, 2018), secretion of extracellular matrix (Noda et al, 2016), and the regulation of transcription factors to be translocated into nucleus (Vuong et al, 2018). Therefore, to better understand the pathogenesis of ciliopathies, it is necessary to elucidate the additional extraciliary roles of these ciliary proteins.…”

“…In contrast, the phenotype of IFT88 in thyroid cancer was more relevant to the mitochondrial oxidative function. Gene expression patterns in IFT88-deficient thyroid cancer cells favored glycolysis and lipid biosynthesis (Lee et al, 2018), which was beyond our understanding of the functions of IFT subunits and prompted us to re-examine the molecular mechanism of ciliopathies.…”