Saul, Dominik

As a member of the 11-gene “death-from-cancer” gene expression signature, ubiquitin-specific protease 22 (USP22) has been considered an oncogene in various human malignancies, including colorectal cancer (CRC). We recently identified an unexpected tumor-suppressive function of USP22 in CRC and detected intestinal inflammation after Usp22 deletion in mice. We aimed to investigate the function of USP22 in intestinal inflammation as well as inflammation-associated CRC. We evaluated the effects of a conditional, intestine-specific knockout of Usp22 during dextran sodium sulfate (DSS)-induced colitis and in a model for inflammation-associated CRC. Mice were analyzed phenotypically and histologically. Differentially regulated genes were identified in USP22-deficient human CRC cells and the occupancy of active histone markers was determined using chromatin immunoprecipitation. The knockout of Usp22 increased inflammation-associated symptoms after DSS treatment locally and systemically. In addition, Usp22 deletion resulted in increased inflammation-associated colorectal tumor growth. Mechanistically, USP22 depletion in human CRC cells induced a profound upregulation of secreted protein acidic and rich in cysteine (SPARC) by affecting H3K27ac and H2Bub1 occupancy on the SPARC gene. The induction of SPARC was confirmed in vivo in our intestinal Usp22-deficient mice. Together, our findings uncover that USP22 controls SPARC expression and inflammation intensity in colitis and CRC.

Aging represents the multifactorial decline in physiological function of every living organism. Over the past decades, several hallmarks of aging have been defined, including epigenetic deregulation. Indeed, multiple epigenetic events were found altered across different species during aging. Epigenetic changes directly contributing to aging and aging-related diseases include the accumulation of histone variants, changes in chromatin accessibility, loss of histones and heterochromatin, aberrant histone modifications, and deregulated expression/activity of miRNAs. As a consequence, cellular processes are affected, which results in the development or progression of several human pathologies, including cancer, diabetes, osteoporosis, and neurodegenerative disorders. In this review, we focus on epigenetic mechanisms underlying aging-related processes in various species and describe how these deregulations contribute to human diseases.

In recent years, climbing sports is on the rise making its Olympic debut in 2021. Physiological traits of professional rock climbers have been intensively studied, while recreational indoor climbers are less investigated, especially regarding grip strength and upper extremity proportions. In this cross-sectional study, we aimed to understand what discerns the recreational climber from disparate recreational athletes. Therefore, we analyzed 50 recreational climbing (30.3 ± 12.7 years, 1.76 ± 0.09 m and 67.0 ± 14.0 kg) and 50 non-climbing athletes (26.4 ± 9.1 years, 1.78 ± 0.09 m and 73.2 ± 12.6 kg) to detect differences in their finger grip strength of seven different pinches. In addition, the upper extremity proportions were measured. Even in recreational climbers, almost all analyzed grips were stronger compared to other athletes (p < 0.05 in all but non-dominant fist, small to moderate effect sizes). Only the grip strength of the whole non-dominant hand was not significantly different (p = 0.17). Interestingly, differences between the dominant and non-dominant hand appeared to be larger in the non-climbing (all p < 0.05, all but one with small effect size) compared to the climbing cohort (pinch I/IV and pinch I/II+III+IV not different and mostly trivial). Circumference measurements showed that 10 cm below the lateral epicondyle, climbers exhibited significantly greater perimeter compared to non-climbing athletes (p < 0.05, small effect size). Our results show that recreational climbers have higher measured grip strength, but less profound differences between the dominant and non-dominant hand.

AbstractBackground and AimsInflammatory bowel diseases are linked to an increased risk of developing colorectal cancer [CRC]. Previous studies suggested that the H2B ubiquitin ligase RING finger protein-20 [RNF20] inhibited inflammatory signaling mediated by the nuclear factor kappa-light-chain-enhancer of activated B cells [NF-κB]. However, the role of RNF40, the obligate heterodimeric partner of RNF20, in the context of inflammation and CRC has not been addressed. Here, we examined the effect of RNF40 loss on CRC cells in vitro and on inflammation and inflammatory signaling in vitro and in vivo.MethodsWe evaluated H2Bub1 levels in human and murine colorectal tumors by immunohistochemistry. Moreover, we correlated H2Bub1 and RNF40 levels in vivo and assessed the consequences of RNF40 depletion on cellular phenotype and gene expression in CRC cells in vitro. Finally, we examined the effect of a colon-specific loss of Rnf40 in a murine model of colitis, and assessed both local and systemic inflammation-associated consequences.ResultsIn vitro studies revealed that the tumorigenic phenotype of CRC cells decreased after RNF40 depletion and displayed gene expression changes related to chromosome segregation and DNA replication, as well as decreased induction of several NF-κB-associated cytokines. This effect was associated with decreased nuclear localization of NF-κB following tumor necrosis factor alpha treatment. Consistently, the colon-specific loss of Rnf40 exerted a protective local, as well as systemic, effect following acute colitis.ConclusionsOur findings suggest that RNF40 plays a central role in the maintenance of tumorigenic features and inflammatory signaling by promoting nuclear NF-κB activity.