The yin and yang interplay between HDAC6 and KDM1 regulates the lysosomal degradation of mutp53 in colon cancer cells undergoing TG-induced ER stress

Abstract

Post-translational modifications (PTMs) play a key role in regulating protein/protein interactions and protein stability, thus influencing protein expression and function. HSPs and p53, including its wtp53 and mutp53 forms, make no exception to this rule, although the impact of PTMs on the regulation of these proteins has not yet been fully elucidated, particularly in the case of mutp53. These proteins, unlike wtp53, can behave as oncogenes, making their targeting an important step for successful anticancer therapy. We previously reported that mutp53 is degraded, preferentially via CMA, in colon cancer cells stressed by long-term TG treatment. Whether TG could induce PTMs and how they could contribute to mutp53 degradation has not yet been investigated and will be explored in this study. Acetylation of mutp53, as well as HSP90, has been reported to promote mutp53 degradation. However, we found that TG promoted deacetylation of mutp53 and HSP90, due to the sustained activity of HDAC6, a PTM that protected mutp53 from degradation. We then found that mutp53 was progressively demethylated by KDM1 at lysine K370 during TG treatment, which facilitated the interaction with HSC70 involved in mutp53 protein degradation via CMA. In conclusion, this study suggests that, in colon cancer cells subjected to stress by TG, mutp53 was degraded as a consequence of demethylation at lysine K370. Therefore, specific epigenetic drugs capable of reducing constitutive methylation and/or increasing acetylation could preemptively target mutp53 and improve the outcome of endoplasmic reticulum stress-inducing treatments in tumors harboring these proteins.