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Aims: Aberrant overactivation/overexpression of NRF2 is implicated as a driving event in tumor progression, which has been attributed to its mutation or inactivation of the inhibitory protein, KEAP1. However, alternative mechanisms responsible for sustained activation of NRF2 are less understood., Main Methods: Human colon cancer cell lines and tissues obtained from colorectal cancer (CRC) patients were used. To examine the expression levels of ARD1 and NRF2, Western blot and immunofluorescence analyses were performed. To investigate the potential relevance of NRF2 and ARD1 to human CRC, NRF2 and ARD1 were individually silenced in human colon cancer cells (HCT-116) by transfection with their specific small interfering RNA (siRNA). To determine the functional role of ARD1 in NRF2 regulation, in situ proximate ligation, co-immunoprecipitation, nano-LC-ESI MS/MS, and in vitro acetylation assays were performed., Key Findings: ARD1 knockdown in human colon cancer cell lines significantly reduced the protein levels of NRF2 without affecting its mRNA expression; however, silencing of NRF2 did not alter ARD1 protein expression. In addition, these two proteins were co-localized and physically interacted with each other both in human colon cancer cells (HCT-116) and human colon tumor tissues. Mechanistically, ARD1 overexpression increased the acetylation levels of NRF2. Moreover, an in vitro acetylation assay and mass spectrometric analysis demonstrated that ARD1 could directly acetylate NRF2. Ectopic expression of mutant forms of ARD1 with defective acetyltransferase activity reduced the stability of NRF2., Significance: In conclusion, ARD1 may potentiate the oncogenic function of NRF2 in human colon cancer by stabilizing this transcription factor., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

SIRT1 is a mammalian NAD + -dependent deacetylase, which is known to be involved in various physiological events, such as adaptive response to environmental stresses including caloric restriction, as well as in aging and cellular senescence. However, recent studies have revealed overexpression of SIRT1 in many different types of human malignancies, particularly colon cancer. Interleukin-1β (IL-1β) is a proinflammatory cytokine that plays a major role in invasiveness, stemness and progression of colon cancer. However, the interaction between IL-1β and SIRT1 in the tumor development and progression remains elusive. In this study, we found that IL-1β induces SIRT1 protein expression in human colon cancer HCT-116 cells. IL-1β-induced SIRT1 upregulation led to enhanced expression of mRNA transcripts of pro-inflammatory cytokines, IL-6 and IL-8 as well as that of IL-1β. Knockdown of SIRT1 prevented IL-1β-induced phosphorylation and nuclear accumulation of c-Jun. Furthermore, pharmacologic inhibition of SIRT1 abrogated clonogenicity and migrative capability of human colon cancer cells stimulated with IL-1β. In summary, IL-1β-induced SIRT1 upregulation stimulates production of proinflammatory cytokines via a nuclear accumulation of c-Jun, leadng to colon cancer growth and progression., (Copyright © 2021 Elsevier Inc. All rights reserved.)