DDX3 modulates cisplatin resistance in OSCC through ALKBH5-mediated m6A-demethylation of FOXM1 and NANOG

Shriwas, Omprakash; Priyadarshini, Manashi; Samal, Sabindra K.; Rath, Rachna; Panda, Sanjay; Majumdar, Saroj Kumar Das; Muduly, Dillip Kumar; Botlagunta, Mahendran; Dash, Rupesh

doi:10.1007/s10495-020-01591-8

Cited by 114 publications

(85 citation statements)

References 32 publications

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“…Chu et al [32] and Feng et al [33] respectively identified the crystal structure of zebrafish ALKBH5 (fALKBH5) and human ALKBH5, which promoted the understanding of the substrate recognition specificity of ALKBH5 and offered a foundation for the development of inhibitors selective for NAOX. In addition, Xu et al [34] affirmed Clear cell renal cell carcinoma Downregulated --- [45] Osteosarcoma --Proliferation and tumor growth PVT1 [40] Oral squamous cell carcinoma --Chemoresistance FOXM1, NANOG [46] the m6A binding pocket of ALKBH5 and the key residues related with m6A recognition through mutagenesis and isothermal titration calorimetry binding experiments. Furthermore, m6A served as a 'conformational marker' , which induced different conformational outcomes in RNAs depending on sequence context and critically impacted its interactions with ALKBH5 [35].…”

Section: The Structure Of Alkbh5mentioning

confidence: 99%

The biological function of m6A demethylase ALKBH5 and its role in human disease

Wang

Wang²,

et al. 2020

Cancer Cell Int

131

113

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Human AlkB homolog H5 (ALKBH5) is a primary m6A demethylase, which is dysregulated and acts as a biological and pharmacological role in human cancers or non-cancers. ALKBH5 plays a dual role in various cancers through regulating kinds of biological processes, such as proliferation, migration, invasion, metastasis and tumor growth. In addition, it takes a great part in human non-cancer, including reproductive system diseases. The underlying regulatory mechanisms of ALKBH5 that relys on m6A-dependent modification are implicated with long non-coding RNA, cancer stem cell, autophagy and hypoxia. ALKBH5 is also an independent prognostic indicator in various cancers. In this review, we summarized the current evidence on ALKBH5 in diverse human cancers or non-cancers and its potential as a prognostic target.

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Section: The Structure Of Alkbh5mentioning

confidence: 99%

The biological function of m6A demethylase ALKBH5 and its role in human disease

Wang

Wang²,

et al. 2020

Cancer Cell Int

131

113

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“…For Cas9 lentivirus generation, we transfected lentiCas9-Blast (Addgene, Cat#52962) along with its packaging psPAX2 and envelop pMD2G in HEK293T cells as lentiviral particles were generated by protocol described in Shriwas et al [7]. Chemoresistant cells were infected with lento Cas9 particles and treated with blastidicines hydrochloride (5 µg/ml, MP biomedical, Cat# 2150477).…”

Section: Methodsmentioning

confidence: 99%

“…OSCC patients tumor and mice tumors were isolated for paraffin embedding for immunohistochemistry following previously described method [7]. Antibodies for RRBP1 (Sigma, cat# HPA011924), Ki67 (Vector, Cat# VP-RM04), cleaved caspase (CST, cat # 9661S), CTGF (Santa Cruz Cat# SC 25440), Survivin (CST Cat# 2808) were used for immunohistochemistry.…”

Section: Methodsmentioning

confidence: 99%

RRBP1 rewires cisplatin resistance in Oral Squamous Cell Carcinoma by regulating YAP-1

Shriwas

Arya

Mohanty

et al. 2020

Preprint

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30Cisplatin-based chemotherapy still remains as one of the primary treatment modalities for 31 OSCC. Several OSCC patients experience relapse owing to development of chemoresistance. To 32 identify key resistance triggering molecules, we performed global proteomic profiling of human 33 OSCC lines presenting with sensitive, early and late cisplatin resistance patterns. From the 34 proteomic profiling study, human RRBP1 was identified to be upregulated in both early and late 35 cisplatin-resistant cells with respect to the sensitive counterpart. Analysis of OSCC patient 36 sample indicates that RRBP1 expression is elevated in chemotherapy-non-responder tumors as 37 compared to chemotherapy-naïve tumors. Knocking out RRBP1 resulted in restoring cisplatin 38 mediated cell death in chemoresistant lines and patient derived cells (PDC). Mechanistically, 39 RRBP1 regulates YAP-1 to induce chemoresistance in OSCC. The chemoresistant PDC 40 xenograft data suggests that knock out of RRBP1 induces cisplatin mediated cell death and 41 facilitates a significant reduction of tumor burden. We also found Radezolid, a novel 42 oxazolidinone antibiotic represses the expression of RRBP1 and restores cisplatin-induced cell 43 death in chemoresistant OSCC. This unique combinatorial approach needs further clinical 44 investigation to target advanced OSCC. Here with for the first time, we uncover the novel role of 45 RRBP1 as potential modulator of cisplatin resistance in advanced OSCC.46 48 developing countries. OSCC is an aggressive form of HNSCC and is the most common cancer 49 among Indian males [1]. Approximately 80,000 new OSCC cases are reported annually with a 50 mortality of 46,000 individuals each year in India. The traditional treatment modalities for 51 advanced OSCC comprises of surgical removal of primary tumors followed by concomitant 52 adjuvant chemoradiotherapy [2]. In addition, neoadjuvant chemotherapy is frequently 53 recommended for surgically unresectable OSCC tumors that reduces tumor and provides more 54 surgical options. Despite having these solutions, the 5-year survival rate of advance tongue 55 OSCC is approximately 50%, indicating a possible resistance to currently available therapeutics. 56 Chemoresistance is one of the important factors for treatment failure in OSCC [3]. Cisplatin 57 alone or in combination with 5-fluorouracil and taxane/docetaxel (TPF) are generally used as 58 chemotherapy regimen for OSCC [4]. But due to chemoresistance development, patients 59 experience relapse which leads to continued tumor growth and metastasis. The chemoresistant 60properties could be attributed to enhanced cancer stem cell population, decreased drug 61 accumulation, reduced drug-target interaction, reduced apoptotic response and enhanced 62 autophagic activities [5]. These hallmarks present the endpoint events, when cancer cell had 63 already acquired chemoresistance. Till date, the causative factors responsible for acquiring 64 chemoresistance in cells are yet not explored. Identifying these molecular triggers ...

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“…Lentivirus was produced by transfection of pLKO.1-shRNA plasmid along with packaging plasmid psPAX2and envelop plasmid pMD2G into HEK293T cells. Lentivirus particles were generated using protocol as described in Shriwas et al 9 . Lentivirus infected cells were incubated with puromycin up to 5 μg/ml for two weeks, stable clones were picked and confirmed by immunoblotting.…”

Section: Methodsmentioning

confidence: 99%

“…Apoptosis and cell death assay was performed by using Annexin V Apoptosis Detection Kit PE (eBioscience™, USA, Cat # 88-8102-74) as described earlier 9 and cell death was monitored using a flow cytometer (BD FACS Fortessa, USA).…”

Section: Methodsmentioning

confidence: 99%

CMTM6 drives cisplatin resistance in OSCC by regulating AKT mediated Wnt signaling

Mohapatra

Shriwas

Mohanty

et al. 2020

Preprint

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41Chemoresistance is one of the important factors for treatment failure in OSCC, which can 42 culminate in progressive tumor growth and metastatic spread. Rewiring tumor cells to undergo 43 drug-induced apoptosis is a promising way to overcome chemoresistance, which can be achieved 44 by identifying the causative factors for acquired chemoresistance. In this study, to explore the 45 key cisplatin resistance triggering factors, we performed global proteomic profiling of OSCC 46 lines representing with sensitive, early and late cisplatin-resistant patterns. The top ranked up-47 regulated protein appeared to be CMTM6. We found CMTM6 to be elevated in both early and 48 late cisplatin-resistant cells with respect to the sensitive counterpart. Analyses of OSCC patient 49 samples indicate that CMTM6 expression is upregulated in chemotherapy-non-responder tumors 50 as compared to chemotherapy-naïve tumors. Stable knockdown of CMTM6 restores cisplatin-51 mediated cell death in chemoresistant OSCC lines. Similarly, upon CMTM6 overexpression in 52 CMTM6KD lines, the cisplatin resistant phenotype was efficiently rescued. Mechanistically, it 53 was found that CMTM6 interacts with membrane bound Enolase-1 and stabilized its expression, 54 which in turn activates the AKT-GSK3β mediated Wnt signaling. CMTM6 triggers the 55 translocation of β-catenin into the nucleus, which elevates the Wnt target pro-survival genes like 56 Cyclin D, c-Myc and CD44. Moreover, incubation with lithium chloride, a Wnt signaling 57 activator, efficiently rescued the chemoresistant phenotype in CMTM6KD OSCC lines. In a 58 patient-derived cell xenograft model of chemoresistant OSCC, knock-down of CMTM6 restores 59 cisplatin induced cell death and results in significant reduction of tumor burden. CMTM6 has 60 recently been identified as a stabilizer of PD-L1 and henceforth it facilitates immune evasion by 61 tumor cells. Herewith for the first time, we uncovered another novel role of CMTM6 as one of 62 the major driver of cisplatin resistance. 63 64 65 66 67 68 69 70 71 72 Head and neck cancer is the sixth most common cancer worldwide with approximately 53,260 73 new cases are being reported in United States alone 1 . Almost 90% of HNSCC cancer cases are 74 Oral squamous cell carcinoma (OSCC) which has emerged as the most common cancer in 75 developing countries. In India, 80000 new OSCC cases are reported in each year with a 76 mortality of ~46000 2 . OSCC patients commonly present with locally advanced (stage III or IV) 77 disease. The treatment modalities of advanced OSCC are surgical removal of primary tumor 78 followed by chemo-radiotherapy 3 . However, neoadjuvant chemotherapy is commonly 79 prescribed for surgically unresectable OSCC tumors that provide more surgical options 4 . In spite 80 of having all these treatment modalities, the 5-year survival rate of advanced tongue OSCC 81 remains less than 50%, which indicates the development of resistance against existing therapy. 82 Chemoresistance is one of the major factors for treatment failure in...

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DDX3 modulates cisplatin resistance in OSCC through ALKBH5-mediated m6A-demethylation of FOXM1 and NANOG

Cited by 114 publications

References 32 publications

The biological function of m6A demethylase ALKBH5 and its role in human disease

The biological function of m6A demethylase ALKBH5 and its role in human disease

RRBP1 rewires cisplatin resistance in Oral Squamous Cell Carcinoma by regulating YAP-1

CMTM6 drives cisplatin resistance in OSCC by regulating AKT mediated Wnt signaling

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