PRESS-NEWS.org - Press Release Distribution
PRESS RELEASES DISTRIBUTION

YAP/TAZ interactions can confer resistance to anti-tumor drug indisulam

YAP/TAZ interactions can confer resistance to anti-tumor drug indisulam
2024-07-29
(Press-News.org) In a healthy human body, tissue growth and development are coordinated by many different mechanisms. Within our bodies, these mechanisms regulate the healthy growth of cells, limit their size and number, and control the timing of cell death through apoptosis. However, when these regulatory pathways are altered, or break down, cell growth and proliferation may increase beyond what is safe and this can lead to cancer. One critical cell growth regulatory mechanism is the Hippo signaling pathway. This pathway regulates the expression of several genes that control cell proliferation and apoptosis via the transcription coactivators YAP/TAZ. Dysregulation of this pathway is commonly seen in several different cancers including head and neck squamous cell carcinoma (HNSCC).

One promising anti-tumor drug is indisulam, a cell cycle inhibitor that inhibits the expression of cell proliferation genes and triggers aberrant mRNA splicing by degrading the RNA-binding protein (RBM39) causing cell death. It has shown promise both in cell cultures and in animal studies. However, clinical trials have shown fewer clear-cut results. Scientists from Hiroshima University Hospital have been researching the reasons behind this resistance to indisulam.

“Clinical trials of indisulam failed to show good response in solid cancer patients but the mechanism of the resistance has not been solved. I wondered if YAP/RBM39 interaction may be involved in the resistance mechanism of indisulam,” said Toshinori Ando, senior lecturer at the Center of Oral Clinical Examination, Hiroshima University Hospital.

In fact, they found “that YAP interacts with RBM39 and confers resistance against indisulam, which is the critical obstruction to be solved for future clinical usage of indisulam,” Ando said. Their research was published on July 15 in Oncogenesis.

A signaling pathway is a series of chemical reactions that are activated by a signal, often environmental. Once begun, each reaction within the pathway is activated in series ending up with the activation or inactivation of a specific cellular function. This allows the body to react to the presence or absence of specific chemicals, such as hormones, by activating or deactivating transcription of certain genes depending on what the cell needs at that moment. The Hippo signalling pathway is a critical pathway that can deactivate the transcription of genes that control cell proliferation by inactivating YAP/TAZ.

The anti-tumor drug indisulam acts by degrading RBM39, a protein that binds to transcription factors, which enhances transcription as well as regulating the mRNA splicing that is integral to the process of gene transcription. By degrading RBM39, indisulam interferes with RBM39’s normal function causing changes in splicing leading to cell death thereby reducing the cell proliferation that can lead to tumor formation.

The Hiroshima University researchers focused on the reactions within the nucleus between the YAP/TAZ transcriptional coactivators and RBM39 to understand what exactly was occurring between them. They also investigated what happens when indisulam was added to determine what was causing the resistance to the anti-tumor drug.

Using proteome analysis, the group identified RBM39’s interactions with YAP/TAZ. They also found evidence that it does promote YAP/TAZ’s transcriptional activity. When indisulam was added it inactivated a focal adhesion kinase (FAK), an enzyme which is very important for cell survival and which caused degradation in RBM39, thereby shutting down the transcription of the cell proliferation genes.

Interestingly, they discovered that the root of indisulam resistance was the activation of YAP/TAZ. When activated it delayed indisulam’s ability to induce the degradation of RBM39 and it reactivated the FAK, thereby reducing the drug’s effectiveness. Activation of YAP/TAZ conferred resistance both in vivo, in cell cultures and in vitro, in mice.

“In this study, we identified RBM39 as a novel YAP/TAZ interactor in the nucleus. Notably, we demonstrated that YAP/TAZ interacts with RBM39 to confer resistance to indisulam. Our findings decipher the resistance mechanism of indisulam, which may aid the development of a novel therapeutic approach for patients with solid cancers including HNSCC,” Ando said.

Going forward, their research will be focusing on “further mechanism of interaction between RBM39 and YAP, thereby developing a new drug targeting the interaction for the patients with solid cancers including HNSCC,” Ando said.

Other contributors include Nanako Kataoka, Tomoaki Shintani and Mikihito Kajiya from the Center of Oral Clinical Examination, Hiroshima University Hospital; Kento Okamoto, Yume Ueda and Souichi Yanamoto from the Department of Oral Oncology, Graduate School of Biomedical and Health Sciences, Hiroshima University; and Mutsumi Miyauchi from the Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical and Health Sciences, Hiroshima University.

This work was supported by JSPS JP20K18477, JP22H03275, and JP24K02645, the “Nozomi h foundation” from the Hiroshima University Foundation, and the JST HIRAKU-Global program.

###

About Hiroshima University

Since its foundation in 1949, Hiroshima University has striven to become one of the most prominent and comprehensive universities in Japan for the promotion and development of scholarship and education. Consisting of 12 schools for undergraduate level and 4 graduate schools, ranging from natural sciences to humanities and social sciences, the university has grown into one of the most distinguished comprehensive research universities in Japan. English website: https://www.hiroshima-u.ac.jp/en

END

[Attachments] See images for this press release:
YAP/TAZ interactions can confer resistance to anti-tumor drug indisulam

ELSE PRESS RELEASES FROM THIS DATE:

Asbestos-related cancer: exaggerated risk perception

2024-07-29
Asbestos, a group of naturally occurring fibrous minerals, has been historically used for its durability and resistance to heat. Despite its advantageous properties, asbestos is a well-documented carcinogen, linked to diseases such as lung cancer (LC) and malignant pleural mesothelioma (MPM). The controversy surrounding the degree of carcinogenicity of different asbestos types, especially chrysotile versus amphibole asbestos, continues to influence scientific and regulatory discussions. This review delves into the various aspects of asbestos-related research, focusing on historical context, risk assessment, environmental ...

Gropp, former NCSA leaders selected for HPCwire’s inaugural ‘35 Legends’ list

2024-07-29
NCSA Director Bill Gropp and two former Center directors were chosen for the first-ever HPCwire “35 Legends” list in celebration of the publication’s 35th anniversary. Thirty-five honorees will be announced each year, selected by HPCwire editors and advisors based on their contributions to the high-performance computing community over the past 35 years and celebrated for the different ways they’ve helped move HPC forward. Gropp, NCSA’s Founding Director Larry Smarr and Former Director Daniel Reed were among the first 17 honorees announced in July. The remaining HPCwire 35 Legends will be ...

The sooner the better: teaching healthy habits in elementary school reduces abdominal fat

The sooner the better: teaching healthy habits in elementary school reduces abdominal fat
2024-07-29
A study led by the Centro Nacional de Investigaciones Cardiovasculares (CNIC) and Fundación SHE, supported by “la Caixa” Foundation, demonstrates that teaching healthy habits through classroom activities helps to prevent the accumulation of abdominal fat during the first school years. The study, published in the Journal of the American College of Cardiology (JACC), is one of the largest contemporary school-based health promotion studies and has one of the most extensive participant follow-up schedules. The conclusions are clear: early intervention to promote healthy habits in elementary school children can be more ...

Exploring the impact of iron overload on mitochondrial DNA in β-thalassemia

Exploring the impact of iron overload on mitochondrial DNA in β-thalassemia
2024-07-29
β-Thalassemia is a genetic disorder characterized by reduced or absent synthesis of the beta chains of hemoglobin, leading to ineffective erythropoiesis and severe anemia. Patients with transfusion-dependent β-thalassemia (TDT) require regular blood transfusions to maintain adequate hemoglobin levels. Non-transfusion-dependent thalassemia (NTDT) patients manage their anemia without regular transfusions but still experience significant health complications. Iron overload is a common and severe complication in both TDT and NTDT patients ...

Fatty acids in umbilical cord blood might cause autism spectrum disorder

Fatty acids in umbilical cord blood might cause autism spectrum disorder
2024-07-29
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects learning capability and social behavior of people. Over the past few decades, awareness regarding ASD has increased, especially regarding its prevalence and effect on the lives of people diagnosed with ASD. However, several aspects related to ASD are not well understood, leaving much to be explored.   Although the exact causes of ASD are unclear, currently available evidence points to neuroinflammation as a major factor. Several studies in mouse models of ASD have hinted at the importance of polyunsaturated ...

Kidney dysfunction may predict sudden cardiac death in patients with heart failure

Kidney dysfunction may predict sudden cardiac death in patients with heart failure
2024-07-29
Patients with congestive heart failure (CHF) having a compromised blood supply, are at greater risk of sudden cardiac death (SCD). With an estimated incidence as high as 22% among these patients, current clinical guidelines recommend using implantable cardioverter defibrillators (ICDs) to help mitigate the risk of SCD. Although the application of ICDs in patients with CHF is backed by substantial evidence, these studies did not include people with chronic kidney disease (CKD), who are an important clinical population. In other ...

Virus that causes COVID-19 is widespread in wildlife, Virginia Tech scientists find

Virus that causes COVID-19 is widespread in wildlife, Virginia Tech scientists find
2024-07-29
SARS-CoV-2, the virus responsible for COVID-19, is widespread among wildlife species, according to Virginia Tech research published Monday (July 29, 2024) in Nature Communications. The virus was detected in six common backyard species, and antibodies indicating prior exposure to the virus were found in five species, with rates of exposure ranging from 40 to 60 percent depending on the species. Genetic tracking in wild animals confirmed both the presence of SARS-CoV-2 and the existence of unique viral mutations with lineages closely matching variants circulating in humans at the time, further supporting human-to-animal transmission, the study found. The highest exposure to SARS ...

Study tracks exposure to air pollution through the day

2024-07-29
There are significant differences in how much people are exposed to air pollution, according to a new study co-authored by MIT scholars that takes daily mobility into account.  The study, based in the Bronx, New York, does not just estimate air pollution exposure based on where people live or work, but uses mobile data to examine where people go during a typical day, building a more thorough assessment of the environment’s impact on them. The research finds exposure to particulate matter 2.5 microns or bigger rises by about 2.4 percent when daily travel patterns are taken into account.  “One of the main strengths of the study is that we ...

UC San Diego researchers use non-invasive technique to record involuntary nervous system

UC San Diego researchers use non-invasive technique to record involuntary nervous system
2024-07-29
A research team led by UC San Diego has, for the first time, shown that a wearable, non-invasive device can measure activity in human cervical nerves in clinical settings. The device records what the team calls Autonomic Neurography (ANG), neural activity from the human vagus and carotid sinus nerves as well as other autonomic nerves found in the skin and muscle of the neck. The vagus nerve is a “superhighway” of the involuntary nervous system, with tendrils extending from the base of the skull through the torso and abdomen to influence digestion, heart rate and the immune system. The vagus nerve ...

Most US voters agree on basic human values – so is polarization exaggerated?

2024-07-29
The vast majority of American voters think alike on what they find important in life, but both Republicans and Democrats fail to recognise their shared views and values, according to new research from the Universities of Bath and Essex. This finding is revealed today in the academic journal Social Psychological and Personality Science less than a month after the US Republican presidential nominee Donald Trump survived an assassination attempt when a gunman shot at him during a campaign rally. “There’s a general perception ...

LAST 30 PRESS RELEASES:

The refrigerator as a harbinger of a better life

Windfall profits from oil and gas could cover climate payments

Heartier Heinz? How scientists are learning to help tomatoes beat the heat

Breaking carbon–hydrogen bonds to make complex molecules

Sometimes you're the windshield: Utah State University researcher says vehicles cause significant bee deaths

AMS Science Preview: Turbulence & thunderstorms, heat stress, future derechos

Study of mountaineering mice sheds light on evolutionary adaptation

Geologists rewrite textbooks with new insights from the bottom of the Grand Canyon

MSU researcher develops promising new genetic breast cancer model

McCombs announces 2024 Hall of Fame inductees and rising stars

Stalling a disease that could annihilate banana production is a high-return investment in Colombia

Measurements from ‘lost’ Seaglider offer new insights into Antarctic ice melting

Grant to support new research to address alcohol-related partner violence among sexual minorities

Biodiversity change amidst disappearing human traditions

New approaches to synthesize compounds for pharmaceutical research

Cohesion through resilient democratic communities

UC Santa Cruz chemists discover new process to make biodiesel production easier, less energy intensive

MD Anderson launches Institute for Cell Therapy Discovery & Innovation to deliver transformational new therapies

New quantum encoding methods slash circuit complexity in machine learning

New research promises an unprecedented look at how psychosocial stress affects military service members’ heart health

Faster measurement of response to antibiotic treatment in sepsis patients using Dimeric HNL

Cleveland Clinic announces updated findings in preventive breast cancer vaccine study

Intergenerational effects of adversity on mind-body health: Pathways through the gut-brain axis

Watch this elephant turn a hose into a sophisticated showering tool

Chimpanzees perform better on challenging computer tasks when they have an audience

New medical AI tool identifies more cases of long COVID from patient health records

Heat waves and adverse health events among dually eligible individuals 65 years and older

Catastrophic health expenditures for in-state and out-of-state abortion care

State divorce laws, reproductive care policies, and pregnancy-associated homicide rates

Emerging roles of high-mobility group box-1 in liver disease

[Press-News.org] YAP/TAZ interactions can confer resistance to anti-tumor drug indisulam