LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function

Area of Science:

• Oncology
• Cell Biology
• Molecular Biology

Background:

• Autophagy modulation is a promising cancer therapy strategy.
• LATS1 and LATS2 kinases are Hippo pathway components with known tumor-suppressive roles.
• The specific role of LATS1 in hepatocellular carcinoma (HCC) remains to be fully elucidated.

Purpose of the Study:

• To investigate the role of LATS1 and LATS2 in hepatocellular carcinoma (HCC) cell survival.
• To determine the mechanism by which LATS1 influences autophagy in HCC cells treated with sorafenib.
• To explore the functional relationship between the Hippo pathway and autophagy in HCC.

Main Methods:

• Investigated LATS1 and LATS2 function in HCC cells.
• Analyzed autophagy induction by sorafenib.
• Examined LATS1's kinase activity in autophagy regulation.
• Assessed Beclin-1 ubiquitination and stabilization by LATS1.
• Studied the impact of Beclin-1 ubiquitination on autophagy.

Main Results:

• LATS1, but not LATS2, exhibits a pro-survival role in HCC cells.
• LATS1 restricts lethal autophagy in HCC cells treated with sorafenib.
• LATS1's regulation of autophagy is independent of its kinase activity.
• LATS1 stabilizes Beclin-1 via K27-linked ubiquitination, promoting inactive dimer formation and inhibiting autophagy.

Conclusions:

• LATS1 plays a pro-survival role in HCC by restricting autophagy.
• LATS1 functions as a scaffold protein, linking the Hippo pathway to autophagy regulation.
• This study uncovers functional divergence between LATS1 and LATS2 and a novel mechanism of autophagy control in HCC.