RBM4 dictates ESCC cell fate switch from cellular senescence to glutamine-addiction survival through inhibiting LKB1-AMPK-axis

Sep 24, 2026

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Cellular senescence acts as a protective barrier against tumorigenesis, yet tumor cells can evade senescence during malignant progression. RBM4 was identified as an ESCC-elevated factor that drives glutamine-dependent survival. RBM4 overexpression promotes a malignant phenotype and helps bypass H-RAS- or doxorubicin-induced senescence, while RBM4 depletion triggers P27-dependent senescence and proliferation arrest via the LKB1-AMPK-mTOR cascade. Mechanistically, RBM4 disrupts the LKB1 complex, recruits TRIM26, and accelerates LKB1 ubiquitination and degradation, maintaining glutamine metabolism and sustaining proliferation. Clinically, high RBM4/low LKB1 predicts poor overall survival and increased sensitivity to CB-839.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages21

Reading Time53 min

AccessFree to download

Introduction

Role of cellular senescence in tumorigenesis

Glutamine metabolism and ESCC

Functions of LKB1 and the LKB1-AMPK axis

Clinical rationale for targeting glutamine dependency

Signal Transduction [and Targeted Therapy](and Targeted Therapy www.nature.com/sigtrans)[ www.nature.com/sigtrans](and Targeted Therapy www.nature.com/sigtrans) RBM4 dictates ESCC cell fate switch from cellular senescenceto glutamine-addiction survival through inhibiting LKB1-AMPK-axis Lei Chen1, Wenjing Zhang 1, Dan Chen2, Quan Yang 1, Siwen Sun3, Zhenwei Dai1, Zhengzheng Li 1, Xuemei Liang4, Chaoqun Chen1, Yuexia Jiao1, Lili Zhi1, Lianmei Zhao5, Jinrui Zhang 1, Xuefeng Liu1, Jinyao Zhao 1, Man Li3 ✉, Yang Wang 1 ✉ and Yangfan Qi 1 ✉ | | Cellular senescence provides a protective barrier against tumorigenesis in precancerous or normal tissues upon distinct stressors. However, the detailed mechanisms by which tumor cells evade premature senescence to malignant progression remain largely elusive. Here we reported that RBM4 adversely impacted cellular senescence to favor glutamine-dependent survival of esophageal squamous cell carcinoma (ESCC) cells by dictating the activity of LKB1, a critical governor of cancer metabolism. The level of RBM4 was speciﬁcally elevated in ESCC compared to normal tissues, and RBM4 overexpression promoted the malignant phenotype. RBM4 contributed to overcome H-RAS- or doxorubicin-induced senescence, while its depletion caused P27-dependent senescence and proliferation arrest by activating LKB1-AMPK-mTOR cascade. Mechanistically, RBM4 competitively bound LKB1 to disrupt the LKB1/ STRAD/MO25 heterotrimeric complex, subsequently recruiting the E3 ligase TRIM26 to LKB1, promoting LKB1 ubiquitination and degradation in nucleus. Therefore, such molecular process leads to bypassing senescence and sustaining cell proliferation through the activation of glutamine metabolism. Clinically, the ESCC patients with high RBM4 and low LKB1 have signiﬁcantly worse overall survival than those with low RBM4 and high LKB1 . The RBM4 high/LKB1 low expression confers increased sensitivity of ESCC cells toglutaminase inhibitor CB-839, providing a novel insight into mechanisms underlying the glutamine-dependency to improve the | | | --- | --- | --- | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | efﬁcacy of glutamine inhibitors in ESCC therapeutics. | | | | | Signal Transduction and Targeted Therapy (2023)8:159 ; [https://doi.org/10.1038/s41392-023-01367-x](https://doi.org/10.1038/s41392-023-01367-x) | | | | | | INTRODUCTION Esophageal carcinoma is one of the most aggressive cancers, which is the seventh in incidence and sixth leading cause of cancer death worldwide.1 More than 70% of global esophageal cancer cases occur in China.2 Esophageal squamous cell carcinoma (ESCC) accounts for ~90% of all diagnosed cases in China. Currently, limited clinical approaches have been identiﬁed for the early diagnosis and treatment of ESCC, leading to an extremely poor prognosis, with the 5-year survival rate ranging from only 10% to 25% .3 Genome-wide screening has identiﬁed multiple genetic alterations in ESCC, including the ampliﬁcation of cyclin D1, which could drive Glutamine-addiction.4,5 Glutamineaddiction or Glutamine (Gln) metabolism has been shown to play critical roles in sustaining tumor rapid growth and metastasis.6–8 Brieﬂy, Glutamine-addiction provides energetic and synthetic needs for cancer cells, maintaining the redox homeostasis and biomass accumulation as a central metabolic hub.8,9 Recently, increased Glutamine metabolism was reported in two independent studies when comparing ESCC with the normal esophageal tissues,5, 10 implying that targeting Glutamine-addiction might offer a promising avenue to treat human ESCC. Therefore, exploring the molecular mechanisms that trigger Glutaminedependency may improve the efﬁcacy of therapeutic target to glutamine metabolism. Serine/threonine kinase STK11 (LKB1) was commonly known asa crucial tumor suppressor with a high frequency of genetic alterations in multiple subtypes of non-sma

FAQs

What role does RBM4 play in ESCC cellular senescence and survival?

RBM4 adversely impacts cellular senescence to favor glutamine-dependent survival of ESCC cells. It promotes a malignant phenotype and supports bypass of senescence induced by oncogenic or drug stress.

How does RBM4 affect the LKB1-AMPK pathway mechanistically?

RBM4 competitively binds LKB1 to disrupt the LKB1/STRAD/MO25 complex, recruits TRIM26, and promotes LKB1 ubiquitination and degradation in the nucleus. This alters downstream LKB1-AMPK signaling.

How do RBM4 and LKB1 expression levels relate to patient outcomes and therapy response?

ESCC patients with high RBM4 and low LKB1 show significantly worse overall survival. The RBM4 high/LKB1 low pattern also confers increased sensitivity to the glutaminase inhibitor CB-839.

Sep 24, 2026

Uploaded by Aria