bims-ectoca 2023-05-07 papers

bioRxiv. 2023 Apr 19. pii: 2023.04.19.537449. [Epub ahead of print]

"Pharmacological inhibition of CLK2 activates YAP by promoting alternative splicing of AMOTL2".

Maya L Bulos, Edyta M Grzelak, Chloris Li-Ma, Emily Chen, Mitchell Hull, Kristen A Johnson, Michael J Bollong.

Yes-associated protein (YAP), the downstream effector of the evolutionarily conserved Hippo pathway, promotes cellular proliferation and coordinates certain regenerative responses in mammals. Small molecule activators of YAP may therefore display therapeutic utility in treating disease states involving insufficient proliferative repair. From a high-throughput chemical screen of the comprehensive drug repurposing library ReFRAME, here we report the identification of SM04690, a clinical stage inhibitor of CLK2, as a potent activator of YAP driven transcriptional activity in cells. CLK2 inhibition promotes alternative splicing of the Hippo pathway protein AMOTL2, producing an exon-skipped gene product that can no longer associate with membrane-bound proteins, resulting in decreased phosphorylation and membrane localization of YAP. This study reveals a novel mechanism by which pharmacological perturbation of alternative splicing inactivates the Hippo pathway and promotes YAP dependent cellular growth.

DOI: https://doi.org/10.1101/2023.04.19.537449

Elife. 2023 May 03. pii: e81173. [Epub ahead of print]12

Shared enhancer gene regulatory networks between wound and oncogenic programs.

Swann Floc'hlay, Ramya Balaji, Dimitrije Stanković, Valerie M Christiaens, Carmen Bravo González-Blas, Seppe De Winter, Gert J Hulselmans, Maxime De Waegeneer, Xiaojiang Quan, Duygu Koldere, Mardelle Atkins, Georg Halder, Mirka Uhlirova, Anne Classen, Stein Aerts.

Wound response programs are often activated during neoplastic growth in tumors. In both wound repair and tumor growth, cells respond to acute stress and balance the activation of multiple programs including apoptosis, proliferation, and cell migration. Central to those responses are the activation of the JNK/MAPK and JAK/STAT signaling pathways. Yet, to what extent these signaling cascades interact at the cis-regulatory level, and how they orchestrate different regulatory and phenotypic responses is still unclear. Here, we aim to characterize the regulatory states that emerge and cooperate in the wound response, using the Drosophila melanogaster wing disc as a model system, and compare these with cancer cell states induced by rasV12scrib-/- in the eye disc. We used single-cell multiome profiling to derive enhancer Gene Regulatory Networks (eGRNs) by integrating chromatin accessibility and gene expression signals. We identify a 'proliferative' eGRN, active in the majority of wounded cells and controlled by AP-1 and STAT. In a smaller, but distinct population of wound cells, a 'senescent' eGRN is activated and driven by C/EBP-like transcription factors (Irbp18, Xrp1, Slow border, and Vrille) and Scalloped. These two eGRN signatures are found to be active in tumor cells, at both gene expression and chromatin accessibility levels. Our single-cell multiome and eGRNs resource offers an in-depth characterisation of the senescence markers, together with a new perspective on the shared gene regulatory programs acting during wound response and oncogenesis.

Keywords: D. melanogaster; computational biology; genetics; genomics; systems biology

DOI: https://doi.org/10.7554/eLife.81173

bioRxiv. 2023 Apr 21. pii: 2023.04.20.537691. [Epub ahead of print]

A core Nrf2 gene set defined through comprehensive transcriptomic analysis predicts drug resistance and poor multi-cancer prognosis.

George Luo, Harshita Kumar, Kristin Aldridge, Stevie Rieger, Ethan Jiang, Ernest R Chan, Ahmed Soliman, Haider Mahdi, John J Letterio.

The Nrf2-KEAP1 pathway plays an important role in the cellular response to oxidative stress and confers protection in diseases associated with chronic inflammation. However, chronic activation of the Nrf2 pathway may contribute to metabolic changes and disease progression in cancer. We investigated the activation of Nrf2 in human cancers and fibroblast cells through KEAP1 inhibition and cancer associated KEAP1/Nrf2 mutations. We define a core set of 14 upregulated Nrf2 target genes from seven RNA-Sequencing databases that we generated and analyzed. Additionally, we validated this universal Nrf2 target gene set through analyses of published databases. An Nrf2 activity score based on expression of these core target genes correlates with resistance to drugs such as PX-12 and necrosulfonamide but not to paclitaxel or bardoxolone methyl. We validated these findings and found Nrf2 activation also led to radioresistance in cancer cell lines. Finally, our Nrf2 score is prognostic for survival for a variety of cancers, an observation validated in additional independent cohorts. These analyses define a core Nrf2 gene set that is robust, versatile, and useful for predicting drug resistance and cancer prognosis.
SIGNIFICANCE: The frequent activation of Nrf2 observed in cancer cells confers protection from oxidative stress, cytotoxic chemotherapeutic agents and radiation. We define a 'Nrf2 gene signature' that is comprised of 14 target genes and faithfully predicts increased Nrf2 activity, selective drug and radiation resistance in cancer cell lines, and a worse clinical prognosis in a variety of human cancers.

DOI: https://doi.org/10.1101/2023.04.20.537691