Circadian rhythm is an autoregulatory rhythm, which is sustained by various mechanisms. The nucleocytoplasmic shuttling of BMAL1 is essential for CLOCK translocation between cytoplasm and nucleus and maintenance of the correct pace of the circadian clock. Here we showed that RAE1 and NUP98 can promote the degradation of BMAL1 and CLOCK. Knockdown of RAE1 and NUP98 suppressed BMAL1 shuttling, leading to cytoplasm accumulation of CLOCK. Furthermore, Chip assay showed that knockdown of RAE1 and NUP98 can enhance the interaction between CLOCK: BMAL1 and E-box region in the promoters of Per2 and Cry1 while reducing its transcription activation activity. Our present study firstly revealed that RAE1 and NUP98 are critical regulators for BMAL1 shuttling.
HDAC3 is involved in deacetylation of histone and non-histone proteins, having a key role in the regulation of gene transcription and also in the process of tumorgenesis. However, how HDAC3 is regulated in cancer remains largely unclear. Here, we showed that PIWIL2 can interact with HDAC3, leading to stabilization of HDAC3 from ubiquitin-mediated degradation by competitive association with E3 ubiquitin ligase Siah2. Furthermore, we found that expression of PIWIL2 enhanced HDAC3 activity via CK2α. PIWIL2 facilitated the interaction between HDAC3 and CK2α, thus exhibiting a promotion on the HDAC3 phosphorylation by CK2α. Further work showed that PIWIL2 could promote cell proliferation and suppress cell apoptosis via regulating HDAC3. Our present study firstly revealed that PIWIL2 can play a role in HDAC3-mediated epigenetic regulation on cancer cell proliferation and apoptosis. These findings provide a novel insight into the roles of PIWIL2 in tumorigenesis.
Human PIWIL2, aka HILI, is a member of PIWI protein family and overexpresses in various tumors. However, the underlying mechanisms of HILI in tumorigenesis remain largely unknown. TBCB has a critical role in regulating microtubule dynamics and is overexpressed in many cancers. Here we report that HILI inhibits Gigaxonin-mediated TBCB ubiquitination and degradation by interacting with TBCB, promoting the binding between HSP90 and TBCB, and suppressing the interaction between Gigaxonin and TBCB. Meanwhile, HILI can also reduce phosphorylation level of TBCB induced by PAK1. Our results showed that HILI suppresses microtubule polymerization and promotes cell proliferation, migration and invasion via TBCB for the first time, revealing a novel mechanism for HILI in tumorigenesis.
IntroductionParoxysmal Nocturnal Hemoglobinuria (PNH) is an acquired clonal disease of hematopoietic stem cells. It is caused by somatic mutation of the X‐linked PIGA gene, resulting in a deficient expression of glycosylphosphatidylinositol‐anchored proteins (GPI‐APs). In this study, we aimed to explore the diagnostic value of next‐generation sequencing (NGS) and potential molecular basis in PNH patients.MethodsGenomic DNA of 85 PNH patients was analyzed by a 114‐gene NGS panel.ResultsMutational analysis of PIGA identified 124 mutations in 92% PNH patients, including 101 distinct mutations and 23 recurrent mutations. Among them, 102 mutations were newly reported. Most mutations were located in exon 2 of PIGA gene, and truncated mutation was the most common one. Other mutations were detected in 26 out of 85 cases, including five cases of DNMT3A variants, four cases of ASXL1 variants, and four cases of U2AF1 variants. Clonal analysis was performed in one case and outlined a linear evolution pattern in classic PNH. There was a positive correlation between number of PIGA mutations and fraction of GPI‐APs deficient granulocytes.ConclusionThe detection of PIGA mutations and additional variants by targeted NGS not only shed light on the genetic characteristics of PNH, but also provided an important reference value in the diagnosis of PNH at molecular level.
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