Prof. Junfang Zheng
Capital Medical University, China
Title: YTHDC1 lactylation regulates its phase separation to enhance target mRNA stability and promote RCC progression
Abstract:
The hypoxic and lactate-enriched microenvironment of renal cell carcinoma (RCC) provides favorable conditions for aberrant lysine lactylation (Kla). However, the functional role and mechanistic basis of Kla in RCC progression remain elusive. Here, we showed an elevated global Kla level in human RCC tissues and cells, which promoted RCC malignancy. Through lactylome analysis of human RCC cells under hypoxia-mimicking conditions, we found that the m6A reader YT521-B homology (YTH) domain-containing 1 (YTHDC1) is modified by Kla at K82. YTHDC1K82la, mediated by p300 under hypoxia, promotes RCC malignancy both in vitro and in vivo. Mechanistically, YTHDC1K82la increases YTHDC1 phase separation, leading to the expansion of nuclear condensates and safeguarding oncogenic transcripts BCL2 and E2F2 from degradation by the poly A-tail exosome targeting (PAXT)-exosome complex in human RCC cells. Our results demonstrated that augmented Kla advances RCC progression by modulating phase separation and thereby regulating the stability of YTHDC1 target genes.
Key Words: Lactylation, YTHDC1, phase-separated condensate, renal cancer, E2F2, BCL2
Biography:
1. Dai
CY#, Tang YG#,
Yang HH, Zheng JF*. YTHDC1 lactylation regulates its phase separation
to enhance target mRNA stability and promote RCC progression. Mol Cell.
2025;85(14):2733-2748.e7.
2.
Tang YG#,
Dai CY#, Yang HH#, Yang X#, Chen ZY, Dou JX,
Zhang LX, Bai T*, Zheng JF*.
KAT8-mediated MDH2 lactylation promotes renal cancer progression by enhancing
mitochondrial function and stress resistance. Int J Biol Macromol. 2025;322(Pt
1):146571.
3.
Zhang LX#, Zhang HN#, Tang YG#, Dai CY, Zheng JF*. SRSF3 suppresses RCC tumorigenesis and progression
via regulating SP4 alternative splicing. Biochim Biophys Acta Mol
Cell Res. 2024:1871(8):119841.
4. Dai CY#, Cao JF#, Tang
YG, Jiang YX, Luo CH*, Zheng JF*. YTHDF3 phase separation regulates ccRCC
development via HSPA13-dependent immune evasion. Cancer Sci.
2024;115(8):2588-2601.
5.
Ma YZ#, Fang ZY#,
Zhang HN#, Qi YJ, Mao YK, Zheng
JF*. PDZK1 suppresses TNBC development and sensitizes TNBC
cells to erlotinib via the EGFR pathway. Cell Death Dis. 2024;15(3):199.
6.
Qi YJ#, Ma YZ#, Peng ZQ, Wang L, Li
LX, Tang YL, He JQ, Zheng JF*.
Long noncoding RNA PENG
upregulates PDZK1 expression by sponging miR-15b to suppress clear cell renal
cell carcinoma cell proliferation. Oncogene. 2020;39(22):4404-4420.
7.
Ma YZ#, Qi YJ#, Wang L,
Zheng ZX, Zhang Y, Zheng JF*.
SIRT5-mediated SDHA desuccinylation promotes clear cell
renal cell carcinoma tumorigenesis. Free Radic Biol Med. 2019;134:458-467.