Targeting Angiogenesis by Blocking the ATM–SerRS–VEGFA Pathway for UV-Induced Skin Photodamage and Melanoma Growth

Abstract

Retinoic acid (RA) has been widely used to protect skin from photo damage and skin carcinomas caused by solar ultraviolet (UV) irradiation, yet the mechanism remains elusive. Here, we report that all-trans retinoic acid (tRA) can directly induce the expression of a newly identified potent anti-angiogenic factor, seryl tRNA synthetase (SerRS), whose angiostatic role can, however, be inhibited by UV-activated ataxia telangiectasia mutated (ATM) kinase. In both a human epidermal cell line, HaCaT, and a mouse melanoma B16F10 cell line, we found that tRA could activate SerRS transcription through binding with the SerRS promoter. However, UV irradiation induced activation of ATM-phosphorylated SerRS, leading to the inactivation of SerRS as a transcriptional repressor of vascular endothelial growth factor A (VEGFA), which dampened the effect of tRA. When combined with ATM inhibitor KU-55933, tRA showed a greatly enhanced efficiency in inhibiting VEGFA expression and a much better protection of mouse skin from photo damage. Also, we found the combination greatly inhibited tumor angiogenesis and growth in mouse melanoma xenograft in vivo. Taken together, tRA combined with an ATM inhibitor can greatly enhance the anti-angiogenic activity of SerRS under UV irradiation and could be a better strategy in protecting skin from angiogenesis-associated skin damage and melanoma caused by UV radiation.

Bladder Cancer‐Derived Small Extracellular Vesicles Promote Tumor Angiogenesis by Inducing HBP‐Related Metabolic Reprogramming and SerRS O‐GlcNAcylation in Endothelial Cells

“…[ 80 ] In this study, we present the first evidence that, in ECs, SerRS can be O‐GlcNAcylated at Ser101, accordingly leading to the suppression of its importin α 5‐mediated nuclear translocation and its increased degradation by ubiquitination, which reduces its competitive binding to the VEGFA proximal promoter with other GC‐TFs and thus facilitates tumor angiogenesis. Although the role of SerRS in the transcriptional suppression of VEGFA has been previously illustrated, [ 51 ] in the present research, we discovered the considerable competitive potential of SerRS for blocking the binding sites of the TFs possessing binding specificities on the GC‐rich region of the VEGFA proximal promoter.…”

“…It has been documented that the angiogenetic role of SerRS relies on its nuclear localization, which attenuates VEGFA expression. [ 50 , 51 ] Consequently, we detected whether SerRS O‐GlcNAcylation affects its nuclear translocation using an IF assay. Intriguingly, we found that administration of PUGNAc strikingly reduced the total levels of SerRS, especially in the nucleus, but we observed the opposite effect in HUVECs whose O‐GlcNAcylation was inhibited by OSMI‐1 (Figure 5H ).…”

Blocking the ATR‐SerRS‐VEGFA pathway targets angiogenesis for UV‐induced cutaneous squamous cell carcinoma

“…In addition, SerRS can sense low oxygen stimulation and be phosphorylated by ATM and ATR at Ser101 and Ser241, resulting in inactivation and weakening of its DNA binding ability, blocking its inhibitory effect on VEGFA 22 . Our research group further found that the UV‐ATM‐SerRS pathway may play an important role in skin photodamage and melanoma 23 . Studies have shown that after UV‐induced DNA damage, the tumor suppressor protein p53 is released from the MDM2‐p53 complex, activated by ATR kinase and FRAP, displaced to the nucleus, triggering cell cycle arrest and promoting DNA repair, aging, or apoptosis 24 .…”

“…22 Our research group further found that the UV-ATM-SerRS pathway may play an important role in skin photodamage and melanoma. 23 Studies have shown that after UVinduced DNA damage, the tumor suppressor protein p53 is released from the MDM2-p53 complex, activated by ATR kinase and FRAP, displaced to the nucleus, triggering cell cycle arrest and promoting DNA repair, aging, or apoptosis. 24 Thus, this study proposes the scientific hypothesis that the UV-ATR-SerRS pathway may play a key role in the development of cSCC by regulating VEGFA and targeting tumor angiogenesis.…”

The Anti-Colon Cancer Effects of Essential Oil of Curcuma phaeocaulis Through Tumour Vessel Normalisation

“…VEGFa is one such fast-response angiogenic factor ( 22 ). Studies have confirmed VEGFa is highly expressed in various tumours in the liver, breast, colon and melanoma cancer ( 23 – 27 ). We observed that OCR inhibited VEGF RNA and protein expression in HUVECs.…”