Mutation of the p53 gene is the most common genetic alteration in human cancer and contributes to malignant process by enhancing transformed properties of cells and resistance to anticancer therapy. Mutant p53 is often highly expressed in tumor cells at least in part due to its increased half-life. However, whether mutant p53 expression is regulated by other mechanisms in tumors is unclear. Here, we found that histone deacetylase inhibitors suppress both wild-type and mutant p53 transcription in time- and dose-dependent manners. Consistent with this, the levels of wild-type and mutant p53 proteins are decreased upon treatment with HDAC inhibitors. Importantly, we found that upon knockdown of each class I HDAC, only HDAC8 knockdown leads to decreased expression of wild-type and mutant p53 proteins and transcripts. Conversely, we found that ectopic expression of wild-type but not mutant HDAC8 leads to increased transcription of p53. Furthermore, we found that knockdown of HDAC8 results in reduced expression of HoxA5 and consequently attenuated ability of HoxA5 to activate p53 transcription, which can be rescued by ectopic expression of HoxA5. Due to the fact that HDAC8 is required for expression of both wild-type and mutant p53, we found that targeted disruption of HDAC8 expression remarkably triggers proliferative defect in cells with a mutant, but not wild-type, p53. Together, our data uncover a regulatory mechanism of mutant p53 transcription via HDAC8 and suggest that HDAC inhibitors and especially HDAC8-targeting agents might be explored as an adjuvant for tumors carrying a mutant p53.

P63, a p53 family member, is expressed as TA and ΔN isoforms. Interestingly, both TAp63 and ΔNp63 are transcription factors, and regulate both common and distinct sets of target genes. p63 is required for survival of some epithelial cell lineages, and lack of p63 leads to loss of epidermis and other epithelia in humans and mice. Here, we explored the role of p63 isoforms in cell proliferation, migration and tubulogenesis by using Madin–Darby Canine Kidney (MDCK) tubular epithelial cells in two- or three-dimensional (2-D or 3-D) culture. We found that like downregulation of p53, downregulation of p63 and TAp63 decreases expression of growth-suppressing genes, including p21, PUMA and MIC-1, and consequently promotes cell proliferation and migration in 2-D culture. However, in 3-D culture, downregulation of p63, especially TAp63, but not p53, decapacitates MDCK cells to form a cyst structure through enhanced epithelial-to-mesenchymal transition (EMT). In contrast, downregulation of ΔNp63 inhibits MDCK cell proliferation and migration in 2-D culture, and delays but does not block MDCK cell cyst formation and tubulogenesis in 3-D culture. Consistent with this, downregulation of ΔNp63 markedly upregulates growth-suppressing genes, including p21, PUMA and MIC-1. Taken together, these data suggest that TAp63 is the major isoform required for tubulogenesis by maintaining an appropriate level of EMT, whereas ΔNp63 fine-tunes the rate of cyst formation and tubulogenesis by maintaining an appropriate expression level of genes involved in cell cycle arrest and apoptosis.

Biological sex is one of the major anthropometric factors which influences 21 physiology, metabolism and health status. We have investigated the effect of sexual 22 dimorphism on the blood lipidome profile in three large population level studies -the 23 Alzheimer's disease neuroimaging initiative -ADNI (n =806), the GeneBank 24 Functional Cardio-Metabolomics cohort (n= 1015) and the Genetics of Lipid lowering 25Drugs and Diet Network -GOLDN (n=422). In total, 355 unique lipids from 15 lipid 26 classes were detected across all three studies using LC-MS. Sixty percent of these 27 lipids differed between men and women in all three cohorts, and up to 87% of all 28 lipids demonstrated sex differences in at least one cohort. ChemRICH enrichment 29 statistics on lipid classes showed that phosphatidylcholines, 30 phosphatidylethanolamines, phosphatidylinositols, ceramides, sphingomyelins and 31 cholesterol esters were found at higher levels in female subjects while 32 triacylglycerols and lysophosphatidylcholines were found at higher levels in male 33 participants across the three cohorts. This strong sex effect on the blood lipidome 34suggests that specific regulatory mechanisms may exist that regulate lipid 35 metabolism in a different manner between men and women. Cohort studies involving 36 blood lipidomics should consider separate analyses for male and female participants 37 instead of combined analyses treating sex as a confounding factor. 38 39 phospholipids, triacylglycerol 40 41 Introduction 42Differences between the sexes are one of the fundamental variations in biology [1]. 43Sex disparities in research can ignore discoveries of the biological mechanisms that 44 are specific to particular sex, leading to missing opportunities in developing new sex-45 specific therapeutic strategies[2]. Sex differences have been observed for gut 46 microbiota[3] and transcriptome [4], suggesting that sex-specific strategies for health 47 improvement are needed. 48Metabolomics has been validated for molecular epidemiology to discover risk factors 49 and biological mechanisms for diseases. Several epidemiological studies have 50 investigated biological sex as a main factor to define a person's metabolome. 51Differential network analysis of metabolomics data for 844 healthy subjects 52 suggested a sex-related variability in branched chain amino acids, ketone bodies, All lipid classes were found to be significantly different between men and women in 131 at least one cohort. The most drastic effects were observed for sphingomyelins, 132 triacylglycerol and phosphatidylcholines in the GOLDN and the GeneBank cohorts. 133Triacylglycerols and lysophosphatidylcholines were consistently higher in men 134 across the three cohorts. Ceramides were higher in men in the GOLDN study but 135 not in the ADNI cohort.

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