JMJD5 interacts with p53 and negatively regulates p53 function in control of cell cycle and proliferation

Abstract

JMJD5 is a Jumonji C domain-containing demethylase/hydroxylase shown to be essential in embryological development, osteoclastic maturation, circadian rhythm regulation and cancer metabolism. However, its role and underlying mechanisms in oncogenesis remain unclear. Here, we demonstrate that JMJD5 forms complex with the tumor suppressor p53 by interacting with p53 DNA-binding domain (DBD), and negatively regulates its activity. Downregulation of JMJD5 resulted in increased expression of multiple p53 downstream genes, such as the cell cycle inhibitor CDKN1A and DNA repair effector P53R2, only in p53-proficient lung cancer cells. Upon DNA damage, the JMJD5-p53 association decreased, and thereby, promoted p53 recruitment to the target genes and stimulated its transcriptional activity. Furthermore, JMJD5 facilitated the cell cycle progression in a p53-dependent manner under both normal and DNA damage conditions. Depletion of JMJD5 inhibited cell proliferation and enhanced adriamycin-induced cell growth suppression in the presence of p53. Collectively, our results reveal that JMJD5 is a novel binding partner of p53 and it functions as a positive modulator of cell cycle and cell proliferation mainly through the repression of p53 pathway. Our study extends the mechanistic understanding of JMJD5 function in cancer development and implicates JMJD5 as a potential therapeutic target for cancer.

Resveratrol induces cell cycle arrest and apoptosis in human eosinophils from asthmatic individuals

“…The results demonstrated that the protein expression levels of p53 and p21 were significantly decreased following resveratrol treatment. Previous studies have indicated that p53 serves an important role in determining the response of cells to different types and levels of stressful stimuli, and regulates downstream cell cycle, cell metabolism, DNA repair and apoptotic signaling pathways (23)(24)(25). In addition, p53 regulates the expression of downstream targets, including p21, which contributes to the modulation of cell cycle progression (26).…”

Depletion of JMJD5 sensitizes tumor cells to microtubule-destabilizing agents by altering microtubule stability

“…32 However, in lung, colon and breast cancers, JMJD5 functions as a putative oncogene that promotes cancer cell proliferation, invasion and cellular metabolism. [29][30][31]47 In the present study, we found that JMJD5 depletion increases the susceptibility of cancer cells to microtubule-destabilizing agents by modulating microtubule stability. A recent study revealed that JMJD5 promotes cancer cell proliferation primarily by inhibiting the nuclear accumulation of p53.…”

“…A recent study revealed that JMJD5 promotes cancer cell proliferation primarily by inhibiting the nuclear accumulation of p53. 47 In addition, p53 has been reported to localize to microtubules and to undergo nuclear transport via dynein in response to DNA damage. 48 Treatment with low concentrations of microtubule-destabilizing agents, such as nocodazole, vincristine and colchicine, enhanced p53 nuclear translocation and p53-mediated activation of downstream target genes.…”

JMJD5 (Jumonji Domain-containing 5) Associates with Spindle Microtubules and Is Required for Proper Mitosis

“…Thus, the effects of JMJD5 on mitosis likely rely on a noncatalytic activity of JMJD5. Coincidentally, a recent report by Huang et al (43) shows that the enzymatic activity of JMJD5 is not required for its cell cycle regulation in A549 cells. However, we have found that mutant JMJD5 also mostly located in the nucleus in interphase cells (data not shown).…”