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Last update 08 May 2025

LAS1L

Last update 08 May 2025

Basic Info

Synonyms

FLJ12525, Las1, LAS1 like ribosome biogenesis factor

+ [3]

Introduction

Required for the synthesis of the 60S ribosomal subunit and maturation of the 28S rRNA (PubMed:20647540). Functions as a component of the Five Friends of Methylated CHTOP (5FMC) complex; the 5FMC complex is recruited to ZNF148 by methylated CHTOP, leading to desumoylation of ZNF148 and subsequent transactivation of ZNF148 target genes (PubMed:22872859). Required for the efficient pre-rRNA processing at both ends of internal transcribed spacer 2 (ITS2) (PubMed:22083961).

Drugs associated with LAS1L

HEN-463

Target

LAS1L

Mechanism

LAS1L inhibitors

Active Org.

Nanjing University of Chinese Medicine

Originator Org.

Nanjing University of Chinese Medicine

Active Indication

Acute Myeloid Leukemia

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with LAS1L

100 Translational Medicine associated with LAS1L

0 Patents (Medical) associated with LAS1L

Literatures (Medical) associated with LAS1L

01 Oct 2024·Cancer Research Communications

USP36 SUMOylates Las1L and Promotes Its Function in Pre–Ribosomal RNA ITS2 Processing

Article

Author: Sears, Rosalie C. ; Yang, Yunhan ; Sun, Xiao-Xin ; Li, Yanping ; Dai, Mu-Shui

AbstractRibosome biogenesis is a highly regulated cellular process requiring a large cohort of accessory factors to ensure the accurate production of ribosomes. Dysregulation of ribosome biogenesis is associated with the development of various human diseases, including cancer. The Las1L–Nol9 endonuclease–kinase complex is essential for the cleavage of the rRNA internal transcribed spacer 2 (ITS2), the phosphorylation of the 5′-hydroxyl end of the resulting precursor, and, thus, the maturation of the 60S ribosome. However, how the Las1L–Nol9 complex is regulated in cells is unclear. In this study, we report that the nucleolar ubiquitin-specific protease USP36 is a novel regulator of the Las1L–Nol9 complex. USP36 interacts with both Las1L and Nol9 and regulates their stability via deubiquitination. Intriguingly, USP36 also mediates the SUMOylation of Las1L, mainly at lysine (K) 565. Mutating K565 to arginine (R) does not affect the levels of Las1L and the formation of the Las1L–Nol9 complex, but abolishes its function in ITS2 processing, as unlike wild-type Las1L, the K565R mutant failed to rescue the defects in the ITS2 processing induced by the knockdown of endogenous Las1L. These results suggest that USP36-mediated Las1L SUMOylation is critical for ITS2 processing and that USP36 plays a critical role in ribosome biogenesis by regulating the Las1L–Nol9 complex.Significance:This study identifies USP36 as a deubiquitinating and small ubiquitin-like modifier ligase dual-function enzyme to mediate Las1L deubiquitination and SUMOylation. Las1L SUMOylation at K565 plays a critical role in pre-rRNA ITS2 processing. Thus, our study reveals a novel downstream pathway for USP36-regulated ribosome biogenesis.

01 Oct 2023·International Journal of Radiation Oncology*Biology*Physics

Dynamic Exosome Analysis to Predict Response to the Combination of SABR and Immunotherapy in Oligoprogressive Disease

Article

Author: Martin, J. Zafra ; Sett, R. Chicas ; Roman, A. ; Villatoro, R ; Perez-Ruiz, E ; Alba, E ; Dubbelman, J. ; Mesas, A. ; Martinez-Galvez, B ; Martin, J Zafra ; Sett, R Chicas ; Garrido, M. ; Benitez, J.C. ; Oliver, J. ; Ramos, I ; Alba, E. ; Medina, J.A. ; Roman, A ; Villatoro, R. ; Benitez, J C ; Oliver, J ; Perez-Ruiz, E. ; Onieva, J.L. ; Rueda-Dominguez, A. ; Barragan, I ; Garrido, M ; Onieva, J L ; Medina, J A ; Dubbelman, J ; Martinez-Galvez, B. ; Ramos, I. ; Barragan, I. ; Mesas, A ; Rueda-Dominguez, A

PURPOSE/OBJECTIVE(S)Up to 80% of metastatic patients face resistance to immune checkpoint inhibitors (ICI). Combined SABR and ICI (I-SABR) can unleash antitumor immune cascades to overcome resistance and improve response with minimal toxicity. This synergy is particularly interesting in the oligoprogressive setting to extend the clinical benefit (CB) of ICI. However, there are no current biomarkers for patient selection. We hypothesize that differential expression of exosomal RNA in liquid biopsy may predict response to I-SABR.MATERIALS/METHODSOngoing prospective multicenter study in two cohorts. Cohort A consists of metastatic patients in oligoprogression to ICI (1-5 extracranial sites) but maintaining the same ICI due to CB and who receive concomitant SABR (35 Gy in 5 fractions, fx) to oligoprogressive sites. Cohort B is a comparative group of oligometastatic patients receiving only SABR in ablative doses. Blood samples are extracted before SABR (T1), after the first (T2) and last (T3) fx, two months post-SABR (T4) and at further progression (TP). Response is evaluated by iRECIST and defined by the objective response rate (ORR) in all lesions (in and out-of-field)- complete and partial responses. For exosome analysis, we perform RNA isolation and small RNA sequencing from plasma. We use Cutadapt, Bowtie and featureCounts to quantify the number of reads of miRNA, small nuclear RNA (snRNA) and small nucleolar RNA (snoRNA). Pairwise differences in expression in responders and non-responders are examined by DESeq2 differential expression analysis. Differentially expressed transcripts are consulted in Ingenuity Pathway Analysis (IPA).RESULTSOf 22 patients recruited, we present preliminary results of the first 10 (8 from cohort A and 2 from B) that had undergone re-evaluation after SABR. Most frequent cancer types were lung (60%) and renal cell (20%). Seventy percent were polymetastatic (>5 lesions) and 90% had a single progressing site. Pembrolizumab (40%) and Nivolumab (30%) were the most frequent ICI. Most lesions for SABR were lung (45%). With a median follow-up of 7.1 months (95% CI, 3.7-10.6) ORR at two months was 60% (6 partial responses, 1 stable disease and 3 progressions). Median progression-free survival was 10.3 months (95% CI, 3.7-not reached) and median overall survival was not reached. Seven patients in cohort A were available for small RNA analysis. We identified 3 miRNA, 24 snRNA and 9 snoRNA that were significantly differentially expressed at T1. Hsa-miR-493, marker of tumor progression, was upregulated in non-responders. RN7SK inhibits LAS1L (a known inductor of metastasis in lung cancer) and was upregulated in responders. SNORD71, which is inhibited by ILF3 (promotor of progression), was also upregulated in responders.CONCLUSIONI-SABR is an effective approach for extending CB of ICI in oligoprogressive patients. Exosomal RNA expression analysis in liquid biopsy is a novel and non-invasive technique that may predict response to this combination and aid in patient selection.

01 Jul 2023·Breast cancer research and treatment

Targeting PELP1 oncogenic signaling in TNBC with the small molecule inhibitor SMIP34.

Article

Author: Liu, Junhao ; Vadlamudi, Ratna K ; Sanchez, John R ; Altwegg, Kristin A ; Yang, Xue ; Sareddy, Gangadhara R ; Viswanadhapalli, Suryavathi ; Pratap, Uday P ; Li, Xiaonan ; Panneerdoss, Durga Meenakshi ; Rao, Manjeet K ; Ebrahimi, Behnam ; Liu, Zexuan

PURPOSETriple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Oncogenic PELP1 is frequently overexpressed in TNBC, and it has been demonstrated that PELP1 signaling is essential for TNBC progression. The therapeutic utility of targeting PELP1 in TNBC, however, remains unknown. In this study, we investigated the effectiveness of SMIP34, a recently developed PELP1 inhibitor for the treatment of TNBC.METHODSTo ascertain the impact of SMIP34 treatment, we used seven different TNBC models for testing cell viability, colony formation, invasion, apoptosis, and cell cycle analysis. Western blotting and RT-qPCR were used to determine the mechanistic insights of SMIP34 action. Using xenograft and PDX tumors, the ability of SMIP34 in suppressing proliferation was examined both ex vivo and in vivo.RESULTSTNBC cells' viability, colony formation, and invasiveness were all decreased by SMIP34 in in vitro cell-based assays, while apoptosis was increased. SMIP34 treatment promoted the degradation of PELP1 through the proteasome pathway. RT-qPCR analyses confirmed that SMIP34 treatment downregulated PELP1 target genes. Further, SMIP34 treatment substantially downregulated PELP1 mediated extranuclear signaling including ERK, mTOR, S6 and 4EBP1. Mechanistic studies confirmed downregulation of PELP1 mediated ribosomal biogenesis functions including downregulation of cMyc and Rix complex proteins LAS1L, TEX-10, and SENP3. The proliferation of TNBC tumor tissues was decreased in explant experiments by SMIP34. Additionally, SMIP34 treatment markedly decreased tumor progression in both TNBC xenograft and PDX models.CONCLUSIONSTogether, these findings from in vitro, ex vivo, and in vivo models show that SMIP34 may be a useful therapeutic agent for inhibiting PELP1 signaling in TNBC.

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LAS1L

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