bims-ectoca 2023-09-17 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2023‒09‒17
eight papers selected by
Ankita Daiya, BITS Pilani

Hippo-YAP/TAZ signaling in breast cancer: Reciprocal regulation of microRNAs and implications in precision medicine.
Natural products modulating epigenetic mechanisms by affecting histone methylation/demethylation: targeting cancer cells.
The TGFβ→TAK1→LATS→YAP1 Pathway Regulates the Spatiotemporal Dynamics of YAP1.
Neoadjuvant chemotherapy enriches for drug-tolerant persisters in PDAC.
Statins improve endothelial function via suppression of epigenetic-driven EndMT.
Different stimuli induce endothelial dysfunction and promote atherosclerosis through the Piezo1/YAP signaling axis.
A short-term three dimensional culture-based drug sensitivity test is feasible for malignant bone tumors.
Knockdown of PRMT1 suppresses the malignant biological behavior of osteosarcoma cells and increases cisplatin sensitivity via c-Myc-mediated BCAT1 downregulation.

Genes Dis. 2024 Mar;11(2): 760-771

Hippo-YAP/TAZ signaling in breast cancer: Reciprocal regulation of microRNAs and implications in precision medicine.

Farzad Sadri, Seyede Fatemeh Hosseini, Zohreh Rezaei, Mohammad Fereidouni.

  Breast cancer is a molecularly heterogeneous disease and the most common female malignancy. In recent years, therapy approaches have evolved to accommodate molecular diversity, with a focus on more biologically based therapies to minimize negative consequences. To regulate cell fate in human breast cells, the Hippo signaling pathway has been associated with the alpha subtype of estrogen receptors. This pathway regulates tissue size, regeneration, and healing, as well as the survival of tissue-specific stem cells, proliferation, and apoptosis in a variety of organs, allowing for cell differentiation. Hippo signaling is mediated by the kinases MST1, MST2, LATS1, and LATS2, as well as the adaptor proteins SAV1 and MOB. These kinases phosphorylate the downstream effectors of the Hippo pathway, yes-associated protein (YAP), and transcriptional coactivator with PDZ-binding motif (TAZ), suppressing the expression of their downstream target genes. The Hippo signaling pathway kinase cascade plays a significant role in all cancers. Understanding the principles of this kinase cascade would prevent the occurrence of breast cancer. In recent years, small noncoding RNAs, or microRNAs, have been implicated in the development of several malignancies, including breast cancer. The interconnections between miRNAs and Hippo signaling pathway core proteins in the breast, on the other hand, remain poorly understood. In this review, we focused on highlighting the Hippo signaling system, its key parts, its importance in breast cancer, and its regulation by miRNAs and other related pathways.

Keywords:  Breast cancer; Hippo signaling; Large tumor suppressor kinase 1; PDZ-binding motif; Yes-associated protein; microRNAs

DOI:  https://doi.org/10.1016/j.gendis.2023.01.017
Br J Pharmacol. 2023 Sep 12.

Natural products modulating epigenetic mechanisms by affecting histone methylation/demethylation: targeting cancer cells.

Dawid Dorna, Adriana Grabowska, Jarosław Paluszczak.

  Many natural products can exert anticancer or chemopreventive activity by interfering with the cellular epigenetic machinery. While a plethora of studies indicate the relevance of affecting DNA methylation and histone acetylation, the influence on the mechanisms related to histone methylation is often overlooked. This may be associated with the lagging evidence that changes in the action of histone methylation writers and erasers and subsequent alterations in the profile of histone methylation are causally related with carcinogenesis. However, recent animal studies have shown that targeting histone methylation/demethylation affects the course of experimentally induced carcinogenesis. Existing data suggest that numerous natural compounds from different chemical groups, including green tea polyphenols and other flavonoids, curcuminoids, stilbene derivatives, phenolic acids, isothiocyanates, alkaloids and terpenes, can affect the expression and activity of crucial enzymes involved in the methylation and demethylation of histone lysine and arginine residues. These activities have been associated with the modulation of cancer-related gene expression and functional changes, including reduced cell proliferation and migration, and enhanced apoptosis in various cancer models. Most studies focused on the modulation of the expression and/or activity of two proteins - EZH2 (a H3K27 methyltransferase) and LSD1 (a H3K4/9 demethylase), or the effects on the global levels of histone methylation marks by the phytochemicals, but data regarding other histone methyltransferases or demethylases are scarce. While the field still remains relatively unexplored, this review aims to explore the impact of natural products on the enzymes related to histone methylation/demethylation, showing their relevance to carcinogenesis and cancer progression.

Keywords:  EZH2; LSD1 ; cancer; histone demethylation; histone methylation; natural compounds

DOI:  https://doi.org/10.1111/bph.16237
Mol Cells. 2023 Sep 13.

The TGFβ→TAK1→LATS→YAP1 Pathway Regulates the Spatiotemporal Dynamics of YAP1.

Min-Kyu Kim, Sang-Hyun Han, Tae-Geun Park, Soo-Hyun Song, Ja-Youl Lee, You-Soub Lee, Seo-Yeong Yoo, Xin-Zi Chi, Eung-Gook Kim, Ju-Won Jang, Dae Sik Lim, Andre J van Wijnen, Jung-Won Lee, Suk-Chul Bae.

  The Hippo kinase cascade functions as a central hub that relays input from the "outside world" of the cell and translates it into specific cellular responses by regulating the activity of Yes-associated protein 1 (YAP1). How Hippo translates input from the extracellular signals into specific intracellular responses remains unclear. Here, we show that transforming growth factor β (TGFβ)-activated TAK1 activates LATS1/2, which then phosphorylates YAP1. Phosphorylated YAP1 (p-YAP1) associates with RUNX3, but not with TEAD4, to form a TGFβ-stimulated restriction (R)-point-associated complex which activates target chromatin loci in the nucleus. Soon after, p-YAP1 is exported to the cytoplasm. Attenuation of TGFβ signaling results in re-localization of unphosphorylated YAP1 to the nucleus, where it forms a YAP1/TEAD4/SMAD3/AP1/p300 complex. The TGFβ-stimulated spatiotemporal dynamics of YAP1 are abrogated in many cancer cells. These results identify a new pathway that integrates TGFβ signals and the Hippo pathway (TGFβ→TAK1→LATS1/2→YAP1 cascade) with a novel dynamic nuclear role for p-YAP1.

Keywords:  ; LATS1/2; RUNX3; TAK1; TGFβ; YAP1; restriction point

DOI:  https://doi.org/10.14348/molcells.2023.0088
Nat Cancer. 2023 Sep 14.

Neoadjuvant chemotherapy enriches for drug-tolerant persisters in PDAC.

DOI: https://doi.org/10.1038/s43018-023-00629-5
Nat Cardiovasc Res. 2023 May;2(5): 467-485

Statins improve endothelial function via suppression of epigenetic-driven EndMT.

Chun Liu, Mengcheng Shen, Wilson L W Tan, Ian Y Chen, Yu Liu, Xuan Yu, Huaxiao Yang, Angela Zhang, Yanxia Liu, Ming-Tao Zhao, Mohamed Ameen, Mao Zhang, Eric R Gross, Lei S Qi, Nazish Sayed, Joseph C Wu.

The pleiotropic benefits of statins in cardiovascular diseases that are independent of their lipid-lowering effects have been well documented, but the underlying mechanisms remain elusive. Here we show that simvastatin significantly improves human induced pluripotent stem cell-derived endothelial cell functions in both baseline and diabetic conditions by reducing chromatin accessibility at transcriptional enhanced associate domain elements and ultimately at endothelial-to-mesenchymal transition (EndMT)-regulating genes in a yes-associated protein (YAP)-dependent manner. Inhibition of geranylgeranyltransferase (GGTase) I, a mevalonate pathway intermediate, repressed YAP nuclear translocation and YAP activity via RhoA signaling antagonism. We further identified a previously undescribed SOX9 enhancer downstream of statin-YAP signaling that promotes the EndMT process. Thus, inhibition of any component of the GGTase-RhoA-YAP-SRY box transcription factor 9 (SOX9) signaling axis was shown to rescue EndMT-associated endothelial dysfunction both in vitro and in vivo, especially under diabetic conditions. Overall, our study reveals an epigenetic modulatory role for simvastatin in repressing EndMT to confer protection against endothelial dysfunction.

DOI: https://doi.org/10.1038/s44161-023-00267-1
Arch Biochem Biophys. 2023 Sep 13. pii: S0003-9861(23)00254-0. [Epub ahead of print] 109755

Different stimuli induce endothelial dysfunction and promote atherosclerosis through the Piezo1/YAP signaling axis.

Jingying Mao, Ronghao Yang, Ping Yuan, Fei Wu, Yan Wei, Yongmei Nie, Chunxiang Zhang, Xiangyu Zhou.

  Vascular endothelial dysfunction is the initial step in atherosclerosis (AS). AS tends to occur at vascular bifurcations and curves, and endothelial cells(ECs) are highly susceptible to injury due to mechanical forces induced by disturbed flow (DF) with inconsistent blood flow directions. However, the pathogenesis of endothelial cell dysfunction in AS remains unclear and needs further study. Here, we found that Piezo1 expression was significantly increased in DF- and oxidized low-density lipoprotein(ox-LDL)-treated HUVECs in vitro and a model of atherosclerotic plaque growth in ApoE-/- mice fed a Western diet. Furthermore, Piezo1 upregulated autophagy levels in the HUVECs model, which was reversed by Piezo1 knockdown with a lentivirus-mediated shRNA system. Mechanistically, the level of Yes-associated protein (YAP), a transcriptional coactivator in the Hippo pathway, was significantly elevated in the DF- and ox-LDL-induced HUVECs model, and this effect was further inhibited by Piezo1 knockdown. Moreover, the Piezo1 agonist Yoda1 inhibited the protein level of microtubule-associated protein 1 light chain 3-II(LC3-II) and increased the protein level of sequestosome1(p62/SQSTM1) in a dose-dependent manner, while significantly promoting the protein expression and nuclear translocation of YAP. The YAP inhibitor CA3 weakened Yoda1-mediated inhibition of autophagy. Our results suggest that Piezo1 may regulate endothelial autophagy by promoting YAP activation and nuclear translocation, thereby contributing to vascular endothelial dysfunction.

Keywords:  Atherosclerosis; Autophagy; Piezo1; Shear stress; YAP

DOI:  https://doi.org/10.1016/j.abb.2023.109755
Hum Cell. 2023 Sep 14.

A short-term three dimensional culture-based drug sensitivity test is feasible for malignant bone tumors.

Hiroaki Goto, Takashi Ohtsu, Mieko Ito, Maiko Sagisaka, Takuya Naruto, Jun-Ichi Nagai, Norihiko Kitagawa, Mio Tanaka, Masakatsu Yanagimachi, Yukihiko Hiroshima, Yohei Miyagi.

  The feasibility of a short-term, three-dimensional (3D) culture-based drug sensitivity test (DST) for surgically resected malignant bone tumors, including osteosarcoma (OS), was evaluated utilizing two OS cell line (KCS8 or KCS9)-derived xenograft (CDX) models. Twenty-three (KCS8) or 39 (KCS9) of 60 tested drugs were likely effective in OS cells derived from a cell line before xenografting. Fewer drugs (19: KCS8, 26: KCS9) were selected as effective drugs in cells derived from a CDX tumor, although the drug sensitivities of 60 drugs significantly correlated between both types of samples. The drug sensitivity of a CDX tumor was not significantly altered after the depletion of non-tumorous components in the sample. In a surgically resected metastatic tumor obtained from a patient with OS, for whom a cancer genome profiling test detected a pathogenic PIK3CA mutation, DST identified mTOR and AKT inhibitors as effective drugs. Of two CDX and six clinical samples of OS and Ewing's sarcoma, DST identified proteasome inhibitors (bortezomib, carfilzomib) and CEP-701 as potentially effective drugs in common. This unique method of in vitro drug testing using 3D-cell cultures is feasible in surgically resected tissues of metastatic malignant bone tumors.

Keywords:  In vitro drug sensitivity test; Malignant bone tumor; Osteosarcoma; Three-dimensional culture; Xenograft

DOI:  https://doi.org/10.1007/s13577-023-00982-8
J Biochem Mol Toxicol. 2023 Sep 13. e23537

Knockdown of PRMT1 suppresses the malignant biological behavior of osteosarcoma cells and increases cisplatin sensitivity via c-Myc-mediated BCAT1 downregulation.

Zhifu Li, Dongdong Meng, Yongyi Liu, Fanggang Bi, Ke Tian, Jianzhong Xu, Jianguang Sun, Chexi Gu, Yu Li.

  Increasing evidence indicated that protein arginine methyltransferase-1 (PRMT1) is an oncogene in multiple malignant tumors, including osteosarcoma (OS). The aim of this study was to investigate the underlying mechanism of PRMT1 in OS. The effects of PRMT1 or BCAT1, branched-chain amino acid transaminase 1 (BCAT1) on OS cell proliferation, invasion, autophagy, and apoptosis in vitro were examined. Moreover, molecular control of PRMT1 on c-Myc or transactivation of BCAT1 on c-Myc was assessed by chromatin immunoprecipitation and quantitative reverse transcription PCR assays. The effects of PRMT1 in vivo were examined with a xenograft tumor model. The results showed that PRMT1 was potently upregulated in OS tissues and cells. Upregulation of PRMT1 markedly increased OS cell proliferation and invasion in vitro and reduced cell apoptosis, whereas PRMT1 silencing showed the opposite effects. Cisplatin, one of the most effective chemotherapeutic drugs, improved cell survival rate by inducing the expression of PRMT1 to downregulate the cisplatin sensitivity. Meanwhile, the cisplatin-induced upregulation of PRMT1 expression caused dramatically autophagy induction and autophagy-mediated apoptosis by inactivating the mTOR signaling pathway, which could be reversed by 3-methyladenine, an autophagy inhibitor, or PRMT1 silencing. PRMT1 could activate c-Myc transcription and increase c-Myc-mediated expression of BCAT1. Furthermore, BCAT1 overexpression counteracted the effects of PRMT1 knockdown on cell proliferation, invasion, and apoptosis. Of note, deficiency of PRMT1 suppressed tumor growth in vivo. PRMT1 facilitated the proliferation and invasion of OS cells, inhibited cell apoptosis, and decreased chemotherapy sensitivity through c-Myc/BCAT1 axis, which may become potential target in treating OS.

Keywords:  BCAT1; PRMT1; c-Myc; cisplatin sensitivity; osteosarcoma

DOI:  https://doi.org/10.1002/jbt.23537