Biology subjects

Hwang-Verslues, W. W.

Publications and source records attributed to Hwang-Verslues, W. W..

5 recordsLinked to original sources

bioRxiv2025

MEX3A control of mitochondrial fitness is essential for ovarian clear cell carcinoma tumorigenesis and liver metastasis

Ovarian cancer (OC) is highly metastatic and chemoresistant. Due to heterogeneity among OC subtypes, the mechanisms underlying OC malignancy and metastasis remain largely unknown. Ovarian clear cell carcinoma (OCCC) accounts for 5-25% of OC and its incidence rate is rising. Liver metastasis is particularly high in OCCC patients and leads to significantly reduced median survival. Why OCCC metastasizes to liver at such high frequency remains elusive. We previously identified MEX3A as a key factor that promotes OCCC tumorigenesis in part by circumventing p53-mediated ferroptosis. Here, we report that MEX3A control of mitochondrial fitness, which occurs independently of p53, is essential for OCCC primary tumor growth and liver metastasis. MEX3A depletion resulted in chronic mitochondrial fragmentation and accumulation of non-functional mitochondria. MEX3A-depleted cells had decreased mitochondrial membrane potential, increased superoxide and decreased NAD+/NADH ratio, resulting in inhibition of oxidative phosphorylation (OXPHOS) and decreased ATP levels. In an environment enriched with mitophagy stressors, such as the liver, MEX3A-depleted OCCC cells had greatly reduced survival due to failure to recover from mitophagy. Consistent with these observations, MEX3A knockdown greatly reduced liver metastasis. Together, these data demonstrate that MEX3A-mediated mitochondrial fitness is a major factor underlying its p53-independent promotion of OCCC tumorigenesis and liver metastasis. Thus, targeting MEX3A will be a promising strategy to inhibit OCCC progression. Statement of significanceUnexpected effects of MEX3A on mitochondrial fitness indicate that the need for high MEX3A expression is an OCCC vulnerability that can be exploited to uncover new treatment strategies.

cancer biology↗

bioRxiv2025

BMAL2 is a druggable target for ARID1A-wildtype ovarian clear cell carcinoma (OCCC)

Ovarian clear cell carcinoma (OCCC) is highly chemo-resistant and has worse clinical outcome at advanced stages than other ovarian cancer subtypes. The most frequent ([~]50%) alterations in OCCC are AT-rich interactive domain 1A gene (ARID1A) mutations which lead to ARID1A deficiency. However, OCCC that retains ARID1A function differs substantially from ARID1A mutated OCCC. Particularly, targeted therapies that sensitize ARID1A-deficient OCCC to DNA damage are largely ineffective against OCCC with wild-type (wt) ARID1A. Thus, it is important to identify druggable targets and develop targeted therapies specifically for ARID1A-wt OCCC. We identified BMAL2 as a critical OCCC oncogene that promotes tumorigenesis by preventing DNA damage from endogenous origins. BMAL2 depletion altered expression of genes in DNA damage repair pathways, including RAD51, a core enzyme of the homologous recombination (HR) pathway. This led to double-stranded break accumulation, decreased cell viability and reduced tumor growth. This dependence on BMAL2 to maintain DNA integrity and cell viability can be a new route to suppress ARID1A-wt OCCC. Consistent with this idea, we found that GW833972A, a cannabinoid receptor agonist, bound BMAL2 with high affinity and facilitated its degradation. This in turn reduced RAD51 expression, leading to an accumulation of DNA damage and decreased cell viability. Xenograft models further demonstrated that GW833972A treatment alone inhibited ARID1A-wt OCCC tumor growth. Together, our findings reveal an essential oncogenic role of BMAL2 and demonstrate that it is an appealing therapeutic target, especially for ARID1A-wt OCCC. Statement of significanceBMAL2 depletion, or degradation by a small molecule, led to DNA damage accumulation, decreased cell viability and reduced tumorigenesis of ARID1A-wildtype ovarian clear cell carcinoma, indicating that BMAL2 is an appealing therapeutic target for treating this malignant disease.

cancer biology↗

bioRxiv2022

BMAL1 and MEX3A co-regulate intestinal stem cell succession

Chemotherapeutic agents, such as 5-fluorouracil (5-FU), often induce intestinal mucositis due to toxicity to rapidly dividing intestinal stem cells (ISCs). Drug delivery at different times of day can alter 5-FU toxicity; however, the underlying biology is unclear. We found that homeostasis and succession between two ISC types, fast proliferating Lgr5+ crypt base columnar (CBC) cells and stress-resistant +4 cells (Bmi1+), are controlled by the circadian clock transcription factor BMAL1 and the BMAL1-regulated RNA-binding protein MEX3A via both direct transcriptional regulation and post-transcriptional control of Lgr5 mRNA stability. Bmal1 knockout in Lgr5+ CBCs reduced MEX3A expression and CBC numbers but increased Bmi1 expression in the crypts. Timing 5-FU delivery when crypt cells had low Lgr5 but peak level of Bmi1 protected ISCs from apoptosis. Together, these findings identify a novel role of BMAL1 in ISC homeostasis and provide a biological explanation for chronotherapeutic chemoprotection.

cell biology↗

bioRxiv2019

Interplay between Desmoglein2 and hypoxia controls intravasation and circulating tumor cell clustering in breast cancer metastasis

Metastasis is the major cause of cancer death. An increased level of circulating tumor cells (CTCs), metastatic cancer cells that have intravasated into the circulatory system, is particularly associated with colonization of distant organs and poor prognosis. However, the key factors required for tumor cell dissemination and colonization remain elusive. We found that high expression of Desmoglein2 (DSG2), a component of desmosome-mediated intercellular adhesion complexes, promoted tumor growth, increased the prevalence of CTC clusters and facilitated distant organ colonization. The dynamic regulation of DSG2 by hypoxia was key to this process as downregulation of DSG2 in hypoxic regions of primary tumors led to elevated epithelial-mesenchymal transition (EMT) gene expression, allowing cells to detach from the primary tumor and undergo intravasation. Subsequent derepression of DSG2 after intravasation and release of hypoxic stress was associated with an increased ability to colonize distant organs. This dynamic regulation of DSG2 was mediated by Hypoxia-Induced Factor1 (HIF1). In contrast to its more widely observed function to promote expression of hypoxia-inducible genes, HIF1 repressed DSG2 by recruitment of the Polycomb Repressive Complex 2 components, EZH2 and SUZ12, to the DSG2 promoter in hypoxic cells. Consistent with our experimental data, DSG2 expression level correlated with poor prognosis and recurrence risk in breast cancer patients. Together, these results demonstrated the importance of DSG2 expression in metastasis and revealed a new mechanism by which hypoxia drives metastasis. Significance StatementDuring metastasis, hypoxia is a major force driving primary tumor cells to disseminate into the circulatory system. The key factors that promote circulating tumor cells (CTC) dissemination and allow them to successfully colonize distal sites are still incompletely known. We found that downregulation of DSG2 in hypoxic tumor allowed single tumor cell dissemination while DSG2 expressing tumors generated more CTC clusters. Re-induction of DSG2 expression in single CTCs may contribute to CTC survival and colonization in distant organs. These findings highlight the importance of DSG2 in breast cancer progression and metastasis.

cancer biology↗

bioRxiv2019

Differential Effects of SUMO1/2 on Circadian Protein PER2 Stability and Function

Posttranslational modification (PTM) of core circadian clock proteins, including Period2 (PER2), is required for proper circadian regulation. PER2 function is regulated by casein kinase 1 (CK1)-mediated phosphorylation and ubiquitination but little is known about other PER2 PTMs or their interaction with PER2 phosphorylation. We found that PER2 can be SUMOylated by both SUMO1 and SUMO2; however, SUMO1 versus SUMO2 conjugation had different effects on PER2 turnover and transcriptional suppressor function. SUMO2 conjugation facilitated PER2-{beta}-TrCP interaction leading to PER2 proteasomal degradation. In contrast, SUMO1 conjugation, mediated by E3 SUMO-protein ligase RanBP2, enhanced CK1-mediated PER2S662 phosphorylation and increased PER2 transcriptional suppressor function. PER2 K736 was critical for both SUMO1- and SUMO2-conjugation. A PER2K736R mutation was sufficient to alter circadian periodicity and reduce PER2-mediated transcriptional suppression. Together, our data revealed SUMO1 versus SUMO2 conjugation acts as an upstream determinant of PER2 phosphorylation and thereby affects the circadian regulatory system and circadian periodicity.

molecular biology↗