TIP60 is required for tumorigenesis in non-small cell lung cancer.

Histone modifications play crucial roles in transcriptional activation, and aberrant epigenetic changes are associated with oncogenesis. Lysine (K) acetyltransferases 5 (TIP60, also known as KAT5) is reportedly implicated in cancer development and maintenance, although its function in lung cancer remains controversial. Here we demonstrate that TIP60 knockdown in non-small cell lung cancer cell lines decreased tumor cell growth, migration, and invasion. Furthermore, analysis of a mouse lung cancer model with lung-specific conditional Tip60 knockout revealed suppressed tumor formation relative to controls, but no apparent effects on normal lung homeostasis. RNA-seq and ChIP-seq analyses of inducible TIP60 knockdown H1975 cells relative to controls revealed transglutaminase enzyme (TGM5) as downstream of TIP60. Investigation of a connectivity map database identified several candidate compounds that decrease TIP60 mRNA, one that suppressed tumor growth in cell culture and in vivo. In addition, TH1834, a TIP60 acetyltransferase inhibitor, showed comparable antitumor effects in cell culture and in vivo. Taken together, suppression of TIP60 activity shows tumor-specific efficacy against lung cancer, with no overt effect on normal tissues. Our work suggests that targeting TIP60 could be a promising approach to treating lung cancer.

Novel TGM5 mutations in acral peeling skin syndrome.

Acral peeling skin syndrome (APSS, MIM #609796) is a rare autosomal recessive disorder characterized by superficial exfoliation and blistering of the volar and dorsal aspects of hands and feet. The level of separation is at the junction of the stratum granulosum and stratum corneum. APSS is caused by mutations in the TGM5 gene encoding transglutaminase-5, which is important for structural integrity of the outermost epidermal layers. The majority of patients originate from Europe and carry a p.(Gly113Cys) mutation in TGM5. In this study, we report both European and non-European families carrying other mutations in the TGM5 gene. In 5 patients, we found 3 novel mutations: c.1001+2_1001+3del, c.1171G>A and c.1498C>T. To confirm their pathogenicity, we performed functional analyses with a transglutaminase activity assay, determined alternative splicing by reverse-transcribed PCR analysis and used databases and in silico prediction tools.

Coincidence of acral peeling skin syndrome and Nagashima-type palmoplantar keratosis in a Japanese pedigree with acral skin peeling.

Acral peeling skin syndrome (APSS; MIM 609796) is a rare genodermatosis characterized by painless focal cutaneous exfoliation of the dorsal hands and feet, typically displaying autosomal recessive inheritance. While cases associated with a founder mutation in TGM5 are relatively common in European Caucasian populations, no APSS cases have been reported from Japan or other East Asian countries. In contrast, Nagashima-type palmoplantar keratosis (NPPK; MIM 615598), caused by variants in SERPINB7, is relatively common in East Asia due to founder mutations. We describe a 27-year-old Japanese woman with spontaneous focal cutaneous exfoliation of the dorsal hand following prolonged glove use, indicative of APSS. Histopathological examination revealed a cleft between the stratum corneum and stratum granulosum and within the horny layer of the epidermis, supporting this diagnosis. However, her mother and maternal uncle exhibited similar symptoms, and there was no reported consanguinity in the patient's parents or grandparents, prompting suspicion of an autosomal dominant genodermatosis. Whole-genome sequencing (WGS) revealed compound heterozygous variants in TGM5 (c.1037G>A and c.684 + 1G>A) as suspected causative variants in the patient, leading to an APSS diagnosis, the first reported in East Asia. On the other hand, her mother and maternal uncle were diagnosed with NPPK due to compound heterozygous pathogenic variants in SERPINB7 (c.796C>T and c.455-1G>A). This case highlights the complexity of diagnosing skin disorders when multiple genodermatoses with similar phenotypes exist within a pedigree. Comprehensive genetic analyses, such as whole-exome sequencing and WGS, are invaluable for identifying causative variants in such complex cases.

Acral peeling skin syndrome resembling epidermolysis bullosa simplex in a 10-month-old boy.

The acral peeling skin syndrome (APSS) is a rare autosomal recessive disorder clinically characterized by asymptomatic desquamation of the skin limited to the hands and feet and histologically by cleavage at the stratum granulosum and stratum corneum level [Kiritsi et al.: J Invest Dermatol 2010;130:1741-1746]. We report on a 10-month-old boy with a history of skin peeling limited to the hands and feet since 2 months of age. Clinical examination revealed erythematous erosions with peripheral desquamation and flaccid blisters. DNA mutation analysis detected two heterozygous TGM5 mutations: c.2T>C, p.M1T in exon 1 and c.337G>T, p.G113C in exon 3 in keeping with the diagnosis of APSS. The clinical presentation of APSS alone might be confusing and strongly resemble epidermolysis bullosa simplex making the differential diagnosis difficult.