Lysyl oxidase-like 3 is required for melanoma cell survival by maintaining genomic stability

Abstract

Lysyl oxidase-like 3 (LOXL3) is a member of the lysyl oxidase family comprising multifunctional enzymes with depicted roles in extracellular matrix maturation, tumorigenesis, and metastasis. In silico expression analyses followed by experimental validation in a comprehensive cohort of human cell lines revealed a significant upregulation of LOXL3 in human melanoma. We show that LOXL3 silencing impairs cell proliferation and triggers apoptosis in various melanoma cell lines. Further supporting a pro-oncogenic role in melanoma, LOXL3 favors tumor growth in vivo and cooperates with oncogenic BRAF in melanocyte transformation. Upon LOXL3 depletion, melanoma cells display a faulty DNA damage response (DDR), characterized by ATM checkpoint activation and inefficient ATR activation leading to the accumulation of double-strand breaks (DSBs) and aberrant mitosis. Consistent with these findings, LOXL3 binds to proteins involved in the maintenance of genome integrity, in particular BRCA2 and MSH2, whose levels dramatically decrease upon LOXL3 depletion. Moreover, LOXL3 is required for efficient DSB repair in melanoma cells. Our results reveal an unexpected role for LOXL3 in the control of genome stability and melanoma progression, exposing its potential as a novel therapeutic target in malignant melanoma, a very aggressive condition yet in need for more effective treatment options.

Maintaining oxidized H3 in heterochromatin is required for the oncogenic capacity of triple-negative breast cancer cells

“…For instance (and as we have previously suggested; (Cebria-Costa et al, 2019), it could protect cells from aberrant activation of the DNA damage response and any consequent cell cycle arrest or cell fate decisions, such as apoptosis or senescence. In fact, another LOX family member, LOXL3, has a major role in the maintenance of genomic stability (Santamaria et al, 2018). We also have demonstrated here that maintenance of this heterochromatin status is required for the ability of TNBC cells to migrate and invade.…”

A 16‐mRNA signature optimizes recurrence‐free survival prediction of Stages II and III gastric cancer

“…LOXL3 is a member of the lysyl oxidase family. It is reported that LOXL3 can regulate genome stability and melanoma progression (Santamaria et al, 2018).…”

The plasma peptides of ovarian cancer

“…However, specific phosphorylations or other post translational modifications of acute phase or other common blood proteins might provide some greater utility than increases in these proteins alone [5, 60–63]. Many of the proteins that varied in ovarian cancer were previously shown to play a role in cancer biology, or were previously established tumor diagnostic or prognostic markers and several have previously been detected in the plasma of cancer: Coagulation factor XIII has been suggested to be a biomarker for screening colorectal cancer [9]; P4HA1 is a prolyl 4-hydroxylase that may be a prognostic marker for glioma [64]; Glipican has been localized to exosomes and previously implicated as a biomarker of cancer [42]; Laminin B2 promotes non-small cell lung cancer [65]; CSR1 is a tumor suppressor gene that activates CPSF3 preventing the interaction of XIAP with caspase [66]; MORN3 is a testes-cancer antigen that recruits the Sirtuin deacetylase that modifies P53 [67]; SIRT1 (Sirtuin) is a histone deacetylase that may regulate tumor formation [68]; Cyclin 1-like (CCN12) plays a role in cell cycle progression and proliferation [69]; NMI is an N-MYC and STAT interactor shown to increase in protein expression with tumor grade and plays a role in cell cycle progression [70]; Increased ITGB1 integrin beta 1 has been shown to be associated with some, but not all, solid cancers [71]; A gene expression array identified NEFM as indicative of the risk of prostate cancer [72]; PLEC1 was shown to promote esophageal cancer cell progression by maintaining the expression of SNAIL [73]; SRGN was show to be expressed in the exosomes of adenocarcinoma by LC–ESI–MS/MS [74]; DHCR reduces cholesterol, may play a role in cancer [75] and selective and potent inhibitors of DHCR have been developed [76]; SMC5 complexes with MMS21 that acts as an E3 ligase required to avoid gross chromosomal rearrangements [77]; Semaphorins such as SEMA6B were strongly down regulated in breast cancer [78]; Lysyl oxidase-like 3 was required for melanoma cell survival [79]; Seizure related 6 homolog (SEZ6L2) showed increased gene expression in primary lung cancer by RT-PCR and Western blot [80].…”