TM4SF19 controls GABP-dependent YAP transcription in head and neck cancer under oxidative stress conditions

Sep 21, 2026

Uploaded by Patrick

Tobacco and alcohol contribute to HPV-negative head and neck squamous cell carcinoma (HPV− HNSCC), yet the mechanisms linking these exposures to tumor biology via oxidative stress remain unclear. Elevated YAP mRNA occurs in HPV− HNSCC independently of YAP gene amplification, and its upregulation is poorly understood. The study reports that oxidative stress promotes YAP transcription through TM4SF19, which regulates GABP transcription factor activity by oxidative-stress–driven TM4SF19 dimerization and ER membrane topology inversion.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages11

Reading Time28 min

AccessFree to download

Significance

Background: HPV− HNSCC risk factors and oxidative stress

Mechanistic link: TM4SF19, GABP, and YAP

Outcomes and therapeutic implications

TM4SF19 controls GABP-dependent YAP transcription in head and neck cancer under oxidative stress conditions Eunbie Shina, Yongsoo Kwona , Eunji Junga , Yong Joon Kimb , Changgon Kima, Semyeong Honga, and Joon Kima,1 Edited by Moshe Oren, Weizmann Institute of Science, Rehovot, Israel; received August 29, 2023; accepted January 4, 2024 Tobacco and alcohol are risk factors for human papillomavirus–negative head and necksquamous cell carcinoma (HPV− HNSCC), which arises from the mucosal epithelium of the upper aerodigestive tract. Notably, despite the mutagenic potential of smoking, HPV− HNSCC exhibits a low mutational load directly attributed to smoking, which implies an undefined role of smoking in HPV− HNSCC. Elevated YAP (Yes-associated protein) mRNA is prevalent in HPV− HNSCC, irrespective of the YAP gene amplification status, and the mechanism behind this upregulation remains elusive. Here, we report that oxidative stress, induced by major risk factors for HPV− HNSCC such as tobacco and alcohol, promotes YAP transcription via TM4SF19 (transmembrane 4 L six family member 19) . TM4SF19 modulates YAP transcription by interacting with the GABP (Guanine and adenine-binding protein) transcription factor complex. Mechanistically, oxidative stress induces TM4SF19 dimerization and topology inversion in the endoplasmic reticulum membrane, which in turn protects the GABPβ1 subunit from proteasomal degradation. Conversely, depletion of TM4SF19 impairs the survival, proliferation, and migration of HPV− HNSCC cells, highlighting the potential therapeutic relevance of targeting TM4SF19. Our findings reveal the roles of the key risk factors of HPV− HNSCC in tumor development via oxidative stress, offering implications for upcoming therapeutic approaches in HPV− HNSCC. oral squamous cell carcinoma | L6 tetraspanin | oxidative stress | YAP Head and neck squamous cell carcinoma (HNSCC) originates from the mucosal epithelium of the anatomical structures constituting the upper aerodigestive tract. It is the sixth most widespread cancer globally and has a mortality rate of 40 to 50%(1). Recently, there has been a marked increase in the incidence of oropharyngeal tumors resulting from human papillomavirus (HPV) infection (2–4). Patients with HPV-positive (HPV+) oro pharyngeal cancer generally exhibit a more favorable prognosis compared to those with HPV-negative (HPV− ) oropharyngeal cancer (5) . The primary risk factors for HPV− HNSCC include tobacco consumption and alcohol abuse (6) . Additionally, areca nut chewing is associated with oral cavity cancer in some Asia-Pacific populations (6). Tobacco, alcohol, and areca nuts produce metabolic by-products that, upon absorption, bind to DNA and cause DNA damage (6) . Intriguingly, a recent analysis of the cancer genome indicated that smoking does not significantly increase the mutational load in oral cancer (7), suggesting mechanisms other than direct DNA damage may be contributing to the promotion of HPV− HNSCC development induced by smoking. Reactive oxygen species (ROS) production is commonly increased in cancer cells due to factors such as high metabolic rate, hypoxia, and gene mutations that affect cell proliferation and mitochondrial function (8) . To counterbalance the elevated ROS levels, the nuclear factor erythroid-2-related factor 2 (NRF2) up-regulates the expression of antioxidant pathway genes (9) . In the presence of environmental factors that further augment ROS levels in cancer cells, the antioxidant system becomes overloaded, leading to transient oxidative damage. Both the gas and tar phases of tobacco contain substantial amounts of free radicals (10, 11), and alcohol exposure independently increases ROS production via oral acetaldehyde formation, irrespective of hepatic metabolism (10, 11) . Oxidative stress can foster cancer development through the activation of oncogenic pathways, disturbance of proteostasis, and induction of DNA damage (12) . Conversely, high levels o

FAQs

How does oxidative stress influence YAP transcription in HPV− HNSCC?

Oxidative stress induced by major risk factors promotes YAP transcription via TM4SF19. TM4SF19 regulates YAP transcription through its interaction with the GABP transcription factor complex.

What role does TM4SF19 play at the molecular level under oxidative stress?

Oxidative stress induces TM4SF19 dimerization and topology inversion in the endoplasmic reticulum membrane. This protects the GABPβ1 subunit from proteasomal degradation.

What is the impact of TM4SF19 depletion on HPV− HNSCC cells?

Depletion of TM4SF19 impairs survival, proliferation, and migration of HPV− HNSCC cells, supporting its potential therapeutic relevance as a target.

Sep 21, 2026

Uploaded by Patrick