Histone H3Y99sulf regulates hepatocellular carcinoma responding to hypoxia.

Histone H3 tyrosine-99 sulfation (H3Y99sulf) is a recently identified histone mark that can cross-talk with H4R3me2a to regulate gene transcription, but its role in cancer biology is less studied. Here, we report that H3Y99sulf is a cancer-associated histone mark that can mediate hepatocellular carcinoma (HCC) cells responding to hypoxia. Hypoxia-stimulated SNAIL pathway elevates the expression of PAPSS2, which serves as a source of adenosine 3'-phosphate 5'-phos-phosulfate for histone sulfation and results in upregulation of H3Y99sulf. The transcription factor TDRD3 is the downstream effector of H3Y99sulf-H4R3me2a axis in HCC. It reads and co-localizes with the H3Y99sulf-H4R3me2a dual mark in the promoter regions of HIF1A and PDK1 to regulate gene transcription. Depletion of SULT1B1 can effectively reduce the occurrence of H3Y99sulf-H4R3me2a-TDRD3 axis in gene promoter regions and lead to downregulation of targeted gene transcription. Hypoxia-inducible factor 1-alpha and PDK1 are master regulators for hypoxic responses and cancer metabolism. Disruption of the H3Y99sulf-H4R3me2a-TDRD3 axis can inhibit the expression and functions of hypoxia-inducible factor 1-alpha and PDK1, resulting in suppressed proliferation, tumor growth, and survival of HCC cells suffering hypoxia stress. The present study extends the regulatory and functional mechanisms of H3Y99sulf and improves our understanding of its role in cancer biology.

Histone tyrosine sulfation by SULT1B1 regulates H4R3me2a and gene transcription.

Tyrosine sulfation is a common posttranslational modification in mammals. To date, it has been thought to be limited to secreted and transmembrane proteins, but little is known about tyrosine sulfation on nuclear proteins. Here we report that SULT1B1 is a histone sulfotransferase that can sulfate the tyrosine 99 residue of nascent histone H3 in cytosol. The sulfated histone H3 can be transported into the nucleus and majorly deposited in the promoter regions of genes in chromatin. While the H3Y99 residue is buried inside octameric nucleosome, dynamically regulated subnucleosomal structures provide chromatin-H3Y99sulf the opportunity of being recognized and bound by PRMT1, which deposits H4R3me2a in chromatin. Disruption of H3Y99sulf reduces PRMT1 binding to chromatin, H4R3me2a level and gene transcription. These findings reveal the mechanisms underlying H3Y99 sulfation and its cross-talk with H4R3me2a to regulate gene transcription. This study extends the spectrum of tyrosine sulfation on nuclear proteins and the repertoire of histone modifications regulating chromatin functions.

Acetyl-CoA Carboxylases and Diseases.

Acetyl-CoA carboxylases (ACCs) are enzymes that catalyze the carboxylation of acetyl-CoA to produce malonyl-CoA. In mammals, ACC1 and ACC2 are two members of ACCs. ACC1 localizes in the cytosol and acts as the first and rate-limiting enzyme in the de novo fatty acid synthesis pathway. ACC2 localizes on the outer membrane of mitochondria and produces malonyl-CoA to regulate the activity of carnitine palmitoyltransferase 1 (CPT1) that involves in the ß-oxidation of fatty acid. Fatty acid synthesis is central in a myriad of physiological and pathological conditions. ACC1 is the major member of ACCs in mammalian, mountains of documents record the roles of ACC1 in various diseases, such as cancer, diabetes, obesity. Besides, acetyl-CoA and malonyl-CoA are cofactors in protein acetylation and malonylation, respectively, so that the manipulation of acetyl-CoA and malonyl-CoA by ACC1 can also markedly influence the profile of protein post-translational modifications, resulting in alternated biological processes in mammalian cells. In the review, we summarize our understandings of ACCs, including their structural features, regulatory mechanisms, and roles in diseases. ACC1 has emerged as a promising target for diseases treatment, so that the specific inhibitors of ACC1 for diseases treatment are also discussed.