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Institute
Fatty acid synthase (FASN) catalyzing the terminal steps in the de novo biogenesis of fatty acids is correlated with low survival and high disease recurrence in patients with bladder cancer. Pyruvate kinase M2 (PKM2) regulates the final step of glycolysis levels and provides a growth advantage to tumors. However, it is unclear whether the change of PKM2 has an effect on FASN and what is the mechanisms underlying. Here we describe a novel function of PKM2 in control of lipid metabolism by mediating transcriptional activation of FASN, showing the reduced expression of sterol regulatory element binding protein 1c (SREBP-1c). We first discovered that PKM2 physically interacts with the SREBP-1c using biochemical approaches, and downregulation of PKM2 reduced the expression of SREBP-1c by inactivating the AKT/mTOR signaling pathway, which in turn directly suppressed the transcription of major lipogenic genes FASN to reduce tumor growths. Furthermore, either PKM2 inhibitor-Shikonin or FASN inhibitor-TVB-3166 alone induced a strong antiproliferative and anticolony forming effect in bladder cancer cell line. The combination of both inhibitors exhibits a super synergistic effect on blocking the bladder cancer cells growth. It provides a new target and scientific basis for the treatment of bladder cancer.
Molecular identification of late and terminal Pleistocene Equus ovodovi from northeastern China
(2019)
The extant diversity of horses (family Equidae) represents a small fraction of that occurring over their evolutionary history. One such lost lineage is the subgenus Sussemionus, which is thought to have become extinct during the Middle Pleistocene. However, recent molecular studies and morphological analysis have revealed that one of their representatives, E. ovodovi, did exist in Siberia during the Late Pleistocene. Fossil materials of E. ovodovi have thus far only been found in Russia. In this study, we extracted DNA from three equid fossil specimens excavated from northeastern China dated at 12,770-12,596, 29,525-28,887 and 40,201-38,848 cal. yBP, respectively, and retrieved three near-complete mitochondrial genomes from the specimens. Phylogenetic analyses cluster the Chinese haplotypes together with previously published Russian E. ovodovi, strongly supporting the assignment of these samples to this taxon. The molecular identification of E. ovodovi in northeastern China extends the known geographical range of this fossil species by several thousand kilometers to the east. The estimated coalescence time of all E. ovodovi haplotypes is approximately 199 Kya, with the Chinese haplotypes coalescing approximately 130 Kya. With a radiocarbon age of 12,770-12,596 cal. yBP, the youngest sample in this study represents the first E. ovodovi sample dating to the terminal Pleistocene, moving the extinction date of this species forwards considerably compared to previously documented fossils. Overall, comparison of our three mitochondrial genomes with the two published ones suggests a genetic diversity similar to several extant species of the genus Equus.
Mitochondrial genomes of Late Pleistocene caballine horses from China belong to a separate clade
(2020)
There were several species of Equus in northern China during the Late Pleistocene, including Equus przewalskii and Equus dalianensis. A number of morphological studies have been carried out on E. przewalskii and E. dalianensis, but their evolutionary history is still unresolved. In this study, we retrieved near-complete mitochondrial genomes from E. dalianensis and E. przewalskii specimens excavated from Late Pleistocene strata in northeastern China. Phylogenetic analyses revealed that caballoid horses were divided into two subclades: the New World and the Old World caballine horse subclades. The Old World caballine horses comprise of two deep phylogenetic lineages, with modern and ancient Equus caballus and modern E. przewalskii forming lineage I, and the individuals in this study together with one Yakut specimen forming lineage II. Our results indicate that Chinese Late Pleistocene caballoid horses showed a closer relationship to other Eurasian caballine horses than that to Pleistocene horses from North America. In addition, phylogenetic analyses suggested a close relationship between E. dalianensis and the Chinese fossil E. przewalskii, in agreement with previous researches based on morphological analyses. Interestingly, E. dalianensis and the fossil E. przewalskii were intermixed rather than split into distinct lineages, suggesting either that gene flow existed between these two species or that morphology-based species assignment of palaeontological specimens is not always correct. Moreover, Bayesian analysis showed that the divergence time between the New World and the Old World caballoid horses was at 1.02 Ma (95% CI: 0.86-1.24 Ma), and the two Old World lineages (I & II) split at 0.88 Ma (95% CI: 0.69-1.13 Ma), which indicates that caballoid horses seem to have evolved into different populations in the Old World soon after they migrated from North America via the Bering Land Bridge. Finally, the TMRCA of E. dalianensis was estimated at 0.20 Ma (95% CI: 0.15-0.28 Ma), and it showed a relative low genetic diversity compared with other Equus species.