ANKRD22, a novel tumor microenvironment-induced mitochondrial protein promotes metabolic reprogramming of colorectal cancer cells

Abstract

Background: The leading cause of poor prognosis in colorectal cancer (CRC) is the presence of colorectal cancer-initiating cells (CCICs). The interplay between the tumor microenvironment (TME) and CRC cells induces reacquisition of initiating cell characteristics, but the underlying mechanisms remain elusive.Methods: Candidate molecules were screened by global differential cDNA expression profiles of CCICs, which were enriched from patient-derived tumor xenograft models. Luciferase reporters and chromatin immunoprecipitation assays were used to explore the mechanism of TME factors regulating the transcription of ANKRD22. The effects of Ankyrin repeat domain-containing protein 22 (ANKRD22) on energy metabolism were monitored by extracellular flux and 13C-based metabolic flux analysis. Mass spectrometry was used to identify the interacting partners of ANKRD22. Morphological changes of CCICs overexpressing ANKRD22 were observed by electron microscopy. The effects of ANKRD22 on mitochondrial lipid metabolism were analyzed by lipidomics.Results: We identified a novel nucleus-encoded mitochondrial membrane protein, ANKRD22, which was upregulated in CCICs. We found that ANKRD22 was induced by the p38/MAX pathway activated by different TME stimuli. As a key transcription factor, MAX promoted the transcription of ANKRD22. Expression of ANKRD22 promoted glycolysis associated with a decrease in ATP/ADP and an increase in AMP/ATP levels, which were related to its interaction with pyruvate dehydrogenase kinase isoform 1 (PDK1) and multiple subunits of ATP synthase. Further, in CCICs, ANKRD22 cooperated with the lipid transport protein, Extended Synaptotagmin-1 (E-Syt1), to transport excess lipids into mitochondria and reduced the number of mitochondria in an autophagy-independent manner, thus meeting the metabolic requirements of CCICs.Conclusion: ANKRD22 induced by TME promotes the metabolic reprogramming of CRC cells. Our study has identified ANKRD22/E-Syt1 as a potential target for eradicating CCICs.

ANKRD22 Drives Rapid Proliferation of Lgr5+ Cells and Acts as a Promising Therapeutic Target in Gastric Mucosal Injury

“…ANKRD22 was widely expressed in the cytoplasm of cells in gastric pits and glands (Figure 1B). Consistent with the intestinal epithelium IHC results, 17 fluorescence colocalization in gastric SGC7901 and BGC823 cells indicated that exogenously expressed ANKRD22 was distributed almost completely in the mitochondria (Figure 1C). Western blot showed that both exogenous and endogenous ANKRD22 were located in purified mitochondria from gastric cancer cells and wild-type C57BL/6 mice gastric tissues.…”

“…We previously reported that ANKRD22 is not involved directly in the canonical Wnt-b-catenin pathway, but results in an increase in the intracellular concentration of Ca 2þ , suggesting that ANKRD22 may affect the canonical Wnt pathway via the noncanonical Wnt-Ca 2þ pathway for the repair of gastric mucosal damage. 17 To determine the relationship between the expression of ANKRD22 and the Wnt-Ca 2þ pathway, we first examined the changes in the intracellular levels of Ca 2þ in Ankrd22 -/mice 24 hours after gastric mucosal injury using the Fluo-4 dye. The Ca 2þ levels were significantly lower in the gastric mucosal epithelial cells of Ankrd22 -/mice than in those of Ankrd22 þ/þ mice (Figure 4C).…”

“…In previous studies using a patient-derived tumor xenograft mouse model and global complementary DNA expression profile scanning, we identified a novel mitochondrial protein, ankyrin repeat domain-containing protein 22 (ANKRD22), which is induced by the tumor microenvironment to promote the reprogramming of colorectal cancer cells as well as the self-renewal of the colorectal cancer-initiating cells. 17 More importantly, pronounced expression of ANKRD22 can be observed in the normal human gastric epithelium, while increased expression is seen in the activated macrophages. 18 However, the specific function of ANKRD22 in the gastric epithelium remains unclear.…”

ANKRD22 enhances breast cancer cell malignancy by activating the Wnt/β-catenin pathway via modulating NuSAP1 expression

“…Ankyrin repeat domain 22 (ANKRD22), a member of the ankyrin repeat (ANKR) family, is constitutively expressed in normal digestive tract epithelium and in tumor cells [7]. ANKR family proteins have been reported to play vital roles in cancer development and progression [8][9][10].…”

Multi-omics analyses of human colorectal cancer revealed three mitochondrial genes potentially associated with poor outcomes of patients

“…In recent years, some studies have identified several mitochondrial genes as potential prognostic biomarkers. However, most studies lack a large-sample cohort, or rarely compare the genes expression between various subtypes of CRC, or the biomarkers have higher correlations with other tumors [ 12 – 16 ], which means more work still need to be done before clinical application.…”