IDH1 mutant structures reveal a mechanism of dominant inhibition

Pioneered by a major cancer ge- nome sequencing project [1] and followed by numerous cancer genomic sequencing studies [2-4], the cytosolic isocitrate dehydrogenase （IDH1） gene and mitochondria isocitrate dehydrogenase （1DH2） gene are found to be frequently mutated in low grade gliomas and secondary glioblastoma multiforme （GBM）, acute myeloid leukemia （AML）, and to a much lower frequency in other types of tumors.

Mechanisms of Hippo pathway in the pancreatic cancer

Pancreatic ductal adenocarcinoma(PDAC)is a lethal,aggressive,and incurable disease.The patients with PDAC are often diagnosed at the advanced stage,leading to poor overall survival because of no current effective treatment.Further exploration of the mechanism is needed urgently to provide insights on the prevention,detection,or intervention of pancreatic cancer.Oncogenic KRAS and mutated tumor suppressor genes serve essential roles in PDAC tumorigenesis.Different groups of scientists indicated that yes-associated protein and transcriptional coactivator with PDZ-binding motif,which are the main effectors of the Hippo pathway,are the center in the development of PDAC.Here,we will focus on the recent advances of the molecular mechanisms of core components in the Hippo kinases cascade and discuss their clinical implications.

The Hippo signalling pathway and its implications in human health and diseases

As an evolutionarily conserved signalling network,the Hippo pathway plays a crucial role in the regulation of numerous biological processes.Thus,substantial efforts have been made to understand the upstream signals that influence the activity of the Hippo pathway,as well as its physiological functions,such as cell proliferation and differentiation,organ growth,embryogenesis,and tissue regeneration/wound healing.However,dysregulation of the Hippo pathway can cause a variety of diseases,including cancer,eye diseases,cardiac diseases,pulmonary diseases,renal diseases,hepatic diseases,and immune dysfunction.Therefore,therapeutic strategies that target dysregulated Hippo components might be promising approaches for the treatment of a wide spectrum of diseases.Here,we review the key components and upstream signals of the Hippo pathway,as well as the critical physiological functions controlled by the Hippo pathway.Additionally,diseases associated with alterations in the Hippo pathway and potential therapies targeting Hippo components will be discussed.

A special issue to mark the 90th Anniversary ofCollege of Life Sciences, Zhejiang University

The College of Life Sciences (CLS) remains one of the most prestigious—and the oldest—colleges in Zhejiang University. This special issue, which includes 16 reviews contributed by our alumni and faculties, is dedicated to mark the 90th Anniversary of CLS.

Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network

Additional sex combs-like 1(ASXL1)interacts with BRCA1-associated protein 1(BAP1)deubiquitinase to oppose the polycomb repressive complex 1(PRC1)-mediated histone H2A ubiquitylation.Germline BAP1 mutations are found in a spectrum of human malignancies,while ASXL1 mutations recurrently occur in myeloid neoplasm and are associated with poor prognosis.Nearly all ASXL1 mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region,resulting in the production of C-terminally truncated mutant ASXL1 proteins.How ASXL1 regulates specific target genes and how the C-terminal truncation of ASXL1 promotes leukemogen-esis are unclear.Here,we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes.We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein in ASXL1 heterozygous leukemia cells,and lose the ability to interact with FOXK1/K2.Specific deletion of the mutant allele eliminates the expression of C-termi-nally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1,thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes,particularly those involved in glucose metabolism,oxygen sensing,and JAK-STAT3 signaling pathways.In addition to FOXK1/K2,we also identify other DNA-bind-ing transcription regulators including transcription factors(TFs)which interact with wild-type ASXL1,but not C-terminally truncated mutant.Our results suggest that ASXL1 mutations result in neomorphic alleles that contribute to leukemogenesis at least in part through dominantly inhibiting the wild-type ASXL1 from interacting with BAP1 and thereby impairing the function of ASXL1-BAP1-TF in regulating target genes and leukemia cell growth.

Metabolic alteration in tumorigenesis

Altered metabolism in cancer was first discovered by Otto Warburg early last century.Although the Warburg Effect has been widely used in tumor detection,relatively little progress had been made in mechanistic understanding of cancer metabolism in the subsequent eight decades.Genetic studies have recently identified mutations in human cancer targeting multiple enzymes involved in intermediate metabolism.One emerging mechanism common to these mutant enzymes is the accumulation of a metabolite that alters the epigenetic control.